4-chloro-4,6-diene-6-halo or lower alkyl steroids

ABSTRACT

4-CHLORO-4,6-DIENE-6-HALO-OR LOWER ALKYL-STEROIDS ARE PREPARED VIA CHLORINANTION OF CORRESPONDING COMPOUNDS UNSUBSTITUTED IN THE 4-POSITION. AFTER THE CHLORINATION COMPOUNDS SATURATED AT THE 1-AND 2-POSITION CAN BE UNSATURATED THEREAT AND COMPOUNDS CONTAINING A 3-OXO GROUP CAN BE CONVERTED TO CORRESPONDING 3-HYDROXY, 3LOWER ALKANOYLOXY OR 3-(1,2-ALKYLENEDIOXY) COMPOUNDS. END-PRODUCTS OF THE INVENTION ARE USEFUL AS EITHER PROGESTATIONAL AGENTS, CORTICOID AGENTS OR ANDROGENIC/ANABOLIC AGENTS DEPENDING UPON THE PARTICULAR DERIVATIVE EMPLOYED.

United States Patent Office 3,707,537. Patented Dec. 26, 1972 ABSTRACTOF THE DISCLOSURE 4-chloro-4,-6-diene-6-haloor lower alkyl-steroids areprepared via chlorination of corresponding compounds unsubstituted inthe 4-position. After the chlorination compounds saturated at the 1- and2-position can be unsaturated thereat and compounds containing a 3-oxogroup can be converted to corresponding 3-hydroxy, 3- lower alkanoyloxyor 3-(1,2-alkylenedioxy) compounds. End-products of the invention areuseful as either progestational agents, corticoid agents orandrogenic/anabolic agents depending upon the particular derivativeemployed.

CROSS REFERENCES TO RELATED APPLICATIONS This application is acontinuation-in-part of Ser. No. 658,602, filed Aug. 7, 1967, nowabandoned which in turn is a continuation-in-part of Ser. No. 604,143filed Dec. 23, 1966, new abandoned which in turn is acontinuation-in-part of Ser. No. 529,200 filed Feb. 23, 1966 nowabandoned.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novelchlorinated steroids and also to certain novel intermediates therefor.In particular, the novel halogenated steroids of this invention arecharacterized in the A and B rings by the features shown in thefollowing partial formula 311 it. I

wherein R is halogen of atomic weight less than 100 or lower alkyl; Q isoxo, hydroxy, lower alkanoyloxy or 1,2-alkylenedioxy of 2 to 4 carbonatoms; and M is the remaining portions of the A and B rings, as well asthe C and D rings of the steroid molecule.

Steroidal compounds having the structural features shown in partialFormula I have been found to have valuable endocrinological properties.

Particularly valuable compounds of Formula I are those wherein themoiety M is of one of the following partial formulas wherein R ishydrogen or fluorine; R is individually hydrogen, hydroxy, lower alkoxy,lower alkanoyloxy, difiuoroor dichloroacetyloxy, or lower alkyl; R, isindividually hydrogen halomethyl, lower alkylidene or lower alkyl or,taken together with R a moiety of the formula C(lower alkyl);

X is an unsaturation between the 1- and 2-position, 2- chloro or alulu-methylene moiety; and n is a whole integer from 0 to 1;

III

wherein R is hydrogen or lower alkanoyl; R is hydrogen, lower alkyl,mono-unsaturated lower alkyl or mono-unsaturated halo-lower alkyl; R ishydrogen or methyl; X is 2-chloro or an unsaturation between the 1- and2-position; n is a whole integer from 0 to l; and Y is provided thatwhen X is an unsaturation, R is methyl;

CHzRn I=0 HaC WV 1: H3O H i XV l 1% wherein R is individually hydrogenor halogen of atomic weight less than R is individually hydrogen, hydroxy, the dihydrogen phosphate ester thereof or alkali metal saltsthereof, or lower alkanoyloxy; R is individually hydrogen, a-hydroxy,lower alkylidene, a-halo or lower alkyl; R is individually loweralkanoyloxy, hydroxy or, taken together with R a moiety of the formula C(lower alkyl):

or, taken together with R a moiety of the formula X' is an unsaturationbetween the 1- and 2-position or 2-chloro; n is a whole integer from 0to 1; Z is individually CH(B-hydroxy), CH(aOR|2)-' or when R ischlorine, CH(B-chlorine), or, taken together with R is an unsaturationbetween the 9- and ll-position or a 9,11-oxido moiety; R is hydrogen orsulfonyloxy; and R and R is each independently lower alkyl.

As used herein the terminology halogen of atomic weight less than 100comprehends bromine, chlorine and fluorine. Lower alkyl comprehends bothstraight and branched chain saturated hydrocarbon moieties having up toeight carbon atoms, such as methyl, ethyl, t-butyl,

n-octyl or the like. Mono-unsaturated lower alkyl comprehends both loweralkenyl and lower alkynyl moieties such as allyl, 2-methylallyl, ethynyland the like, and mono-unsaturated halo-lower alkyl comprehends bromo orchloro moieties such as 2-chloroethynyl, 3-chloro-2- methylallyl and thelike. Lower alkoxy comprehends moieties which can be designated -O(loweralkyl); that is, moieties such as methoxy, ethoxy, and the like. Loweralkylidene indicates a straight or branched chain hydrocarbon moiety theterminal carbon atom of which has two free valence bonds such asmethylene, isopropylidene and the like; methylene being especiallypreferred. Lower alkanoyl similarly comprehends residue of lower alkanecarboxylic acids, such as acetyl, butyryl, caprylyl or the like and1,2-alkylenedioxy of 2 to 4 carbon atoms comprehends moieties such asethylenedioxy and the like. Alkali metal has its usual meaning andincludes such metals as lithium, sodium and potassium. When used as partof the definition of R halo comprehends chloro or fiuoro. Sulfonyloxycomprehends lower alkyl sulfonyloxy moieties such as mesyloxy andarylsulfonyloxy moieties such as tosyloxy. Preferred compounds are thosewherein R is chlorine, fluorine or lower alkyl of up to four carbonatoms. Especially preferred are those compounds wherein R is chlorine,fluorine or methyl. Also preferred are compounds wherein Q is acetoxy,ethylenedioxy or oxo.

Compounds which combine the features of partial Formulas I and III or IVwherein Y or Z is are useful as intermediates, for example, forcorresponding compounds wherein Y or Z is .c. ll

This conversion can be effected by known means. Similarly compoundswhich combine the features of partial Formulas I and II wherein R ishydroxy can be esterified, and compounds which combine the features ofpartial Formulas I and III wherein R is lower alkanoyl can be convertedinto the corresponding free hydroxy compounds. Thus, such compounds areuseful as intermediates, as are other of the novel compounds of thisinvention as illustrated or described herein or as will be apparent toone skilled in the art of steroid chemistry.

The compounds of this invention can be prepared from compounds of theformula CH(fi-hydroxy) it is preferable to protect the hydroxy groupprior to chlorination, for example, via acylation to form thecorresponding llfl-formyloxy or trifluoroacetoxy compound. After the cho ination the llpydroxy compound can be generated by conventional means.When the 9-position is substituted with halogen such as fluorine, i.e.,R is other than hydrogen, chlorination may be undertaken withoutprotecting the llp-hydroxy moiety, if present. Products of partialFormulas I and III wherein R is lower alkanoyl can be converted tocorresponding compounds wherein R is hydrogen via ketalization, if Q isoxo, followed by reduction with lithium aluminum hydride yieldingcompounds wherein R is hydrogen and Q is 1,2-alkylenedioxy. The compoundso-obtained, if desired, can be deketalized by conventional means, forexample, by treatment with mineral acid. It is, however, preferred tomake the latter compounds directly via chlorination of startingmaterials of partial Formulas III and V wherein R is hydrogen. Inaddition to the foregoing, other known techniques can be used to protectlabile groups prior to the chlorination procedure.

The chlorination procedure is part of this invention and is suitablyeffected by intramixing chlorine and a reaction medium which containsthe starting steroid represented by the partial Formula V, preferably insolution. The chlorination proceeds in accordance with the followingreaction sequence, the exact reaction route followed being determined bythe particular process conditions employed.

M PM XIII wherein R and M are as previously defined.

Both the 4EJe-dichloro-6-substituted-A compounds represented by thepartial Formula XIII and the 4-chloro- 6-substituted-4,6-diene compoundsrepresented by the partial Formula Ia are endocrinologically useful aswill be more fully described hereinafter. Further, the former compoundsare useful as intermediates in the preparation of the latter compounds.Thus, depending on which class of products is sought to be prepared,viz, the A compounds of the partial Formula XIII or the A compounds ofthe partial Formula Ia, process step (a) or steps (a) and (c) or step(b) can be alternatively followed.

When it is desired to prepare the 4e,7e-diCh1OIO-6-Sllbstituted-Acompounds represented by the partial Formula XIII, the 4,6-dienestarting steroids represented by partial Formula V are treated withchlorine in accordance with step (a). This step may be facilitated bythe addition of a catalytic amount of anhydrous mineral or organic acid.Preferred are the hydrohalic acids, e.g., hydrogen chloride. Thechlorination may be carried out in an inert organic reaction medium, forexample, ethers such as lower alkyl ether, for example, ethyl ether ordioxane; chlorinated hydrocarbons such as chloroform, carbontetrachloride, ethylene chloride or methylene chloride or the like. Thechlorine can be introduced into the reaction medium by conventionaltechniques, e.g., a solution containing the chlorine can be introducedinto the reaction mixture. A chlorine-containing lower alkanoic acidsolution, for example, chlorine in propionic acid is suitable for thispurpose. The treatment with chlorine is suitably effected at lowtemperatures, preferably between 40 C. and room temperature, moreadvantageously between -30 C. and 0 C.

A preferred class of the A compounds represented by the partial FormulaXIII are those having 4e,6,7e-trichloro grouping. Especially preferredare the 4s,6,7e-triChlOIO-A compounds combined with structures of theFormula II wherein R is hydrogen, R is acetoxy, n is and R is methyleneor hydrogen. The 4e,7e-dichloro-o-substituted- A compounds representedby Formula XHI are endocrinologically useful per se as describedhereinafter and are additionally useful as intermediates for thecorresponding 4-chloro-6-substituted-4,6-diene compounds represented byFormula la.

The substituted-A compounds represented by the partial Formula XIII canbe converted to the 4-chloro-6- substituted-4,6-diene compounds ofFormula Ia. The conversion can be effected in accordance with step (c)of the above reaction sequence by treating the former compounds with adehydrochlorinating agent under either neutral, basic or acidicconditions. Thus, the dehydrochlorination can be carried out under basicconditions, i.e., in the presence of a proton acceptor such as, forexample, nitrogen-containing heterocyclic bases, e.g., pyridine,picoline or the like; or tri-lower alkylamines, e.g., triethylamine; andalkali metal inorganic bases such as alkali hydroxides, e.g., sodiumhydroxide or alkali bicarbonates, e.g., sodium bicarbonate. Whenconducted under basic conditions a suitable solvent which may beemployed for the conversion is the base itself. However, other solventssuch as inert organic solvents, for example, ethers such as lower alkylethers, for example, ethyl ether or dioxane; chlorinated hydrocarbons,such as chloroform or carbon tetrachloride, may also be employed.Alternatively, the dehydrohalogenation can be effected under acidicconditions using an aqueous mineral acid, preferably a hydrohalic acid,e.g., hydrochloric acid. Preferred solvents for the reaction, whencarried out under acidic conditions are water miscible ethers such astetrahydrofuran, dioxane or glyme; water soluble amides such asdimethylformamide. The dehydrohalogenation can also be conducted in theabsence of acid or base, i.e., under neutral conditions, by using forexample, N,N-di-lower alkyl-lower alkanoyl-amides such asdimethylformamide or dimethylacetamide. Dimethylsulfoxide may also besuitably employed.

The dehydrochlorination carried out in accordance with step (c) of thereaction scheme is suitably conducted between temperatures of about 0and 100 C., although a temperature range of 0 to 50 C. is preferred. Ifthe steroid being subjected to the dehydrochlorination process issubstituted with an alkanoyloxy moiety, the preferred proton acceptor isa nitrogen-containing heterocyclic base with pyridine being especiallypreferred.

Alternatively, if desired, the 4-chloro-6-substituted-4,6- dienecompounds represented by the partial Formula Ia can be prepared directlyfrom the 4,6-diene Starting compounds of Formula V, without isolatingthe A compounds of the partial Formula XHI in accordance with step (b)of the reaction sequence. The conversion is effected by chlorinating thecompounds of Formula V in the presence of a proton acceptor, forexample, an N,N-di-lower alkyllower alkanoyl-amide, such asdimethylformamide or dimethylacetamide; a lower alkyleue oxide such asethylene oxide or propylene oxide, or the like; in a solvent such aslower alkanoic acids, e.g., acetic acid or propionic acid. It should benoted that when the 4-chloro-6-substituted- 4,6-diene compoundsrepresented by Formula Ia are prepared directly from the startingmaterials of Formula V, without isolating the A steroids of Formula XHI,the proton acceptor is initially present in the reaction medium when thechlorination is effected.

The proton acceptor can also serve as the solvent for the startingmaterial represented by the partial Formula V. Alternatively, andpreferably, the reaction medium can contain other solvents. Thesesolvents can be any convenient inert organic solvents, for example,ethers such as lower alkyl ethers, for example, ethyl ether, or dioxane;chlorinated hydrocarbons such as chloroform or carbon tetrachloride; orthe like. The chlorine can be introduced into the reaction mixture byconventional techniques, e.g., a solution containing the chlorine can beintroduced into the reaction mixture. A chlorine-containing loweralkanoic acid solution, for example, chlorine in propionic acid, issuitable for this purpose. The treatment with chlorine is suitablyeffected at a low temperature, preferably between about 40 C. and roomtemperature, more advantageously between about -30 C. and about 0 C.Another embodiment is to treat the starting reactant of Formula V withchlorine in carbon tetrachloride using chloroform as a solvent for thestarting material. The reaction is carried out preferably between about0 C. and room temperature, followed by removal of the solvent andtreatment with a heterocyclic nitrogen-containing base such aspyrindine, picoline or the like.

The above-described chlorination procedure is a part of this invention.The facile manner in which it can be conducted and the good yieldsobtainable therewith are notable inasmuch as conventional processesutilizing 4- chloroA or 4-ch1oro-6-substituted-A steroids have failed toyield detectable, appreciable amounts of 4-chloro -6-R -4,6-diene-3-onesteroid product, wherein R is chlorine.

Compounds wherein Q is oxo can be converted into compounds wherein Q is1,2-alkylenedioxy subsequent to chlorination via conventional means, forexample, via reaction with a 1,2-alkylene glycol in the presence of anacid catalyst such as para-toluene-sulfonic acid. For example, ethyleneglycol can be used and yields a compound wherein Q is ethylenedioxy.Also, compounds wherein Q is oxo can be converted into compounds whereinQ is hydroxy by conventional reduction means such as treatment withlithium aluminum tri-t-butoxyhydride or sodium borohydride. In thosestarting materials containing a 20- 0x0 moiety it is preferable tohinder this moiety prior to the reduction in order to prevent said20-oxo moiety from being reduced. Such hindrance can be effected byknown means, for example, by introducing an ester moiety in thel7u-position or by formation of the bis-methylenedioxy derivative.Furthermore, compounds wherein Q is hydroxy can be converted intocompounds wherein Q is lower alkanoyloxy by conventional loweralkanoylating means as lower alkanoic anhydride in pyridine. Moreover,compounds wherein n is 0 can be converted into compounds wherein n is 1and X or X' is an unsaturation between the land Z-position by meansknown per se such as treatment with selenious acid. Also, as aby-product of the 4-chlorination procedure of this invention ofcompounds wherein R and M have the same meaning as above and in themoiety M, n is 0; it is possible to obtain compounds of the formulawherein R has the same meaning as above and M has the same meaning as Mabsent the carbon atoms at the 1- and 2-position.

Such 2,4-dichloro compounds of Formula Vc, which can also be obtained bydirect chlorination of a compound of Formula I wherein n is 0, can beconverted into compounds of Formula I wherein n is 1 and X or X' is anunsaturation between the 1- and 2-position by dehydrochlorinati-on meansknown per se such as by treatment with lithium chloride indimethylformamide.

Compounds which combine the features of partial Formulas I and IIwherein R Q, R R R X and n have the same meaning as above are useful asprogestational agents. When R is hydrogen or hydroxy, the compounds canbe administered parenterally, and when R is lower alkoxy, loweralkanoyloxy, difluoror dichloroacetyloxy or lower alkyl, the compoundscan be administered orally or parenterally. Preferred compounds arethose wherein R is chlorine or fluorine; Q is oxo, hydroxy, acetoxy orethylenedioxy; R and n have the same meaning as above; R is loweralkoxy, lower alkanoyloxy or lower alkyl; R; is hydrogen, methylene,ethyl or methyl and X is an unsaturation between the 1- and 2- position.

Compounds which combine the features of partial Formulas I and IIIwherein Q, R R R 11 and Y have the same meaning as above, R ismono-unsaturated lower al-kyl or mono-unsaturated halo-lower alkyl and Xis an unsaturation between the 1- and 2-position are also useful asprogestational agents. These compounds can be administered orally orparenterally. Preferred compounds of this group are those wherein R ischlorine or fluorine, Q is oxo, hydroxy, acetoxy or ethylenedioxy, R ishydrogen or lower alkanoyl, R is hydrogen or methyl, Y is CH and R isethynyl, 2-chloroethynyl, allyl, 2- methallyl, or l-propynyl.

Those compounds which combine the features of partial Formulas I and IIIwherein R Q, R R n and Y have the same meaning as above and R ishydrogen or lower alkyl and X' is an unsaturation between the 1- and2-position are useful as androgenic/ anabolic agents. Of these compoundsthose wherein R is hydrogen can be administered parenterally and thosewherein R is lower alkyl can be administered orally or parenterally. Ofthese compounds useful as androgenic/ anabolic agents those wherein R ischlorine or fluorine; Q is oxo, hydroxy, acetoxy or ethylenedioxy; R ishydrogen; R is lower alkyl; R7 is hydrogen or methyl; n is O and Y is CHare preferred. If a high ratio of anabolic to androgenic activity isdesired, such compounds wherein R is hydrogen are preferred.

Those compounds which combine features of partial Formulas I and IVwherein R Q, R R R and R have the same meaning as above are useful ascorticoid agents when n is 0 or when n is 1, X is an unsaturationbetween the 1- and 2-position, and when Z is CH CO--, CH(,B-hydroxy)- orCH(p-chlorine)--. Those compounds wherein Z is CH are useful asmineralocorticoids and those compounds wherein Z is CO, CH({3-hydroxy)or CH(fl-chlorine)- are useful as glucocorticoids, i.e., asantiinfiammatory and thymolytic agents. The compounds useful asmineralocorticoids can be administered orally or parenterally, and thosecompounds useful as anti-inflammatory and thymolytic agents can beadministered orally, parenterally, or particularly when Z containsS-hydroxy or B-chlorine, topically. of those compounds useful asanti-inflammatory and thymolytic agents especially preferred are thosewherein R is chlorine or fluorine; Q is oxo, hydroxy, acetoxy orethylenedioxy; R is halogen; R is the dihydrogen phosphate ester orlower alkanoyloxy; R is ahydroxy, methylene, methyl or ethyl; R ishydroxy, or taken together with R 2,2-isopropylenedioxy; n is 0 and Z isCH(t3-hydroxy).

Those compounds combining the features of partial Formula I and partialFormuals II, III or IV which are not endocrinologically useful, asdescribed above, are useful as intermediates for the preparation of suchendocrinologically useful compounds as described herein. The compoundsof this invention which combine the features of partial Formula 1 andpartial Formulas II, III or IV which are useful as progestational orcorticoid agents are marked by an especially high degree of activity.Also, those compounds indicated above to be the preferred compoundsamong the endocrinologically useful compounds particularly possess ahigh degree of activity.

Compounds which combine the features of partial Formula XIII or otheroxo derivatives as defined by the variable Q and partial Formula IIwherein R R R R.;, X and n have the same meaning as above are useful asprogestational agents. Compounds which combine the features of partialFormula XIII or other oxo derivatives as defined by the variable Q andpartial Formula IV wherein R R R R R have the same meaning as above areuseful as corticoid agents when n is 0 or when n is 1, X is anunsaturation between the 1- and 2-position, and when Z is CH CO,CHQS-hydroxy)- or --CH( 8-chlorine)-. Those compounds wherein Z is CO,-CH(fl-hydroxy)- or CH(B- chlorine)-are useful as glucocorticoids, i.e.,as antiinfiammatory and thymolytic agents.

The 4,7dichloro-6-substituted-A compounds which combine the features ofpartial Formulas II and XIII or partial Formulas IV and XIII can bepharmaceutically administered in a similar fashion as described above,as the corresponding steroids having the4-chloro-6-substituted-4,6-diene partial steroid configuration ofFormula I.

In addition to the 4,6-disubstituted-4,6-dienes of Formula I describedabove, certain intermediates useful in their preparation are novel andare a part of this invention. Such compounds are, for example, those ofthe formula HaC OR14 wherein R is hydrogen or lower alkanoyl; R' islower alkyl; and R is a halogen of atomic weight less than 100.

The compounds of Formula VI can be prepared by a three-step procedurestarting from compounds of the formula VII wherein R and R' each has thesame meaning as above.

VIII

wherein R and R' each has the same meaning as above.

The compound of Formula VIII is then selectively oxidized, once againaccording to known procedures, for example, with monoperphthalic acid,to yield a compound of the formula OR 11.0 L

H H3O 1 l H I 0: I

wherein R is hydrogen or acetyl. In addition to being useful asintermediates for corresponding 4,6-dichloro-4,6-diene compounds ofFormula I, compounds of Formula X are endocrinologically useful. Thecompound of Formula X wherein R is hydrogen is useful as an anabolic andandrogenic agent, whereas the compound of Formula X wherein R is acetylis useful as an antiandrogenic agent. The latter compound can beconverted into the former which can be prepared from the corresponding6-chloro-3-methoxy-3,S-diene compound via treatment with t-butylchromate, manganese dioxide or the like oxidizing agent. In the samemanner other '6-ch1oro-4,6-dien-3-one compounds of Formula V can beprepared from corresponding 6-chloro-3- lower alkoxy-3,5-diene compoundswhich in turn can be obtained from 6-chloro-4-en-3-one compounds viatreatment of the latter with tri(lower alkyl)-orthofoformate. Theprocedures described in this paragraph are known and can be conductedaccording to the known techniques.

Compounds which combine the features of partial Formulas I and IIwherein R is hydrogen can be converted into compounds of Formulas I andII where R is hydroxy. In one procedure a compound of 'Formulas I and 11wherein R is hydrogen and Q is oxo is treated with acetic anhydride andperchloric acid yielding the enol acetate compound of the formulawherein R X and n have the same meaning as above.

XII

wherein R X and n have the same meaning as above.

Via acidic or basic hydrolysis a compound of Formula XII can beconverted to a compound of Formulas I and II wherein R is hydroxy. Theabove procedures utilizing compounds of Formulas XI and XII asintermediates are known reaction procedures and can be conductedaccording to known techniques.

In still another aspect, this invention relates to a method and novelintermediates prepared thereby which is particularly suitable forpreparing corticoid type compounds which are formed by combining thestructures of partial Formulas I and IV wherein R Q, R R Z, X and n aredefined as aforesaid; R is hydroxy; and R is methylene. The startingmaterials which can be employed to prepare these l6-methylene,l7-hydroxy corticoid type compounds are characterized by having astructure of the partial Formula V and further defined so as thevariable R is hydroxy and R is hydrogen, such as, for example,6-chloro-17,2l-dihydroxy-pregna 4,6 diene 3,11,20- trione-Zl-acetate.The process comprises first introducing a A bond into the startingsteroid reactant. The A bond can be introduced into the ring system byforming the C-20 semicarbazone by known means, dehydrating the thusobtained semicarbazone intermediate by means of strong acid, preferablytrifiuoroacetic acid, then removing the semicarbazide moiety by means ofpyruvic acid in a 50% aqueous acetic acid solution and thus regeneratingthe 20-oxo group. A 16-methyl group is next introduced into the systemby a sequential process of reacting the thus obtained A-4,6-diene-steroid with diazomethane and then pyrolyzing the thusobtained intermediate. The reaction is etfected by known means, i.e., byadding a solution of diazomethane conveniently prepared fromnitrosomethyl urea in ether to the steroid reactant in an inert organicreaction medium, such as an ether, preferably tetrahydrofuran. Thereaction can conveniently be conducted at room temperature. The 16-methyl-A -4,6-diene-6-substituted corticoid is obtained by pyrolyzingthe 16,17-methyleneazo intermediate by heating at a temperature of aboutC. to about 200 C. The A -16-methylcorticoid is then chlorinatedemploying methods described earlier in this application. Thechlorination can be conducted so as to yield directly the M' --6-substituted-4-chloro corticoids or 4,7-dichloro-A-6-substituted-corticoids in accordance with earlier described methods(viz steps (a), (b) and (c) of the reaction scheme). The lattercompounds are next reacted by epoxidizing the A bond so as to form thecorresponding 1'6u,17a-oxido derivative. The conversion is effected bymeans of a suitable epoxidizing agent such as peroxytrifluoroacetic acidin a suitable inert organic solvent, preferably a chlorinatedhydrocarbon such as methylene chloride. The peroxytrifluoroacetic acidsolution may be prepared in situ by adding hydrogen peroxide totrifluoroacetic acid anhydride. The reaction can be convenientlyconducted at a temperature range of about 20 C. to +25 C. The resulting4,7-dichloro-A -6-substituted- 16a,l7a-oxido derivatives are treatedwith pyridine to give the corresponding 4-chloro-An-substituted-16a,17uoxido intermediates. The desired16-methylene-17-hydroxy corticoid end-product having the partial FormulaIV and further characterized by R as methylene and R as hydroxy is thenobtained by cleaving the 16a,170coxido such as trifluoroacetic acid inan anhydrous inert organic solvent, preferably a hydrocarbon such asbenzene.

When preparing certain pregnane-type compounds, viz, those formed bycombining the structures of Formulas I and II wherein X, n, R, and R aredefined as aforesaid; R is hydroxy and [R is methylene, it has beenfound preferable to introduce the 17-hydroxy moiety after chlorinationof the starting reactants of Formula V has been effected. An especiallypreferred method is to employ as a starting reactant, the corresponding16-methylene-17- alkanoyloxy derivative. Thus, in one embodiment,17aacetoxy-4,6-dichloro-16-methylenepregna-4,6-diene 3,20- dione isfirst selectively reduced to yield the corresponding 'C-3 hydroxyderivative using lithium aluminum tritertiary butoxyhydride, in ethersolvent, e.g., tetrahydrofuran at room temperature. The thus obtained17a-ace toxy-4,6-dichloro-16-methylene-pregna-4,6-diene 3 hydroxy--oneis then hydrolyzed using an alkali metal hydroxide, e.g., potassiumhydroxide in a lower alkanol solvent, preferably methanol at roomtemperature to yield the corresponding 3,17-dihydroxy derivative. Ifdesired, the C-3 oxo group can be regenerated by oxidation with asuitable oxidizing agent, such as manganese dioxide in an inert organicsolvent, preferably, a chlorinated hydrocarbon, such as chloroform atroom temperature to yield the desired3,20-diketo-16-methylene-17a-hydroxy-pregnane derivative. Further, ithas been found that 16-methylene-l7-alkanoyloxy-pregna-4,6-dienes whichare additionally unsaturated at the C1 position, e.g., 17-acetoxy-4,6-dichloro-lfi-methylenepregna-1,4,6-triene-3,20 dione can beconverted to the corresponding 16-methylene-l7ahydroxy derivativedirectly by hydrolyzing with an alkali metal hydroxide without firstreducing the C-3 oxo moiety as was found necessary with pregnane-typecompounds discussed above, which are saturated at the C-1 position.

The starting materials of partial Formula V represent a known class ofcompounds which can be prepared, for example, by insertion of anunsaturation between the 6- and 7-position of corresponding 3-oxo-A-6-substituted compounds. The preparation of certain starting materialsof partial Formula V is specifically illustrated herein and otherstarting materials of partial Formula V can be prepared in the samemanner.

Compounds which combine the features of partial Formulas I and IVwherein R is other than hydrogen can be prepared from compounds whichcombine the features of partial Formulas I and IV wherein Z is CFOR12)and R is hydrogen via means known per se. For example, the lla-hydroxygroup can be converted to a sulfonyloxy moiety such as rnesyloxy,tosyloxy or the like, and such ll-sulfonyloxy compound can then beconverted to the corresponding M -compound which upon treatment with abrominating agent such as 'N-bromoacetamide is converted into thecorresponding 9a-bromo-11 3-hydroxy compound. Alternatively, treatmentof the A -compound with a chlorinating agent such as a solution ofchlorine in carbon tetrachloride yields a 9a,11fi-dichloro compound.Treatment of the 9a-bromo-1l5-hydroxy compound with a dehydrobrominatingagent such as an alkali metal hydroxide solution yields thecorresponding 9,11 6- oxido compound which upon treatment with hydrogenfluoride is converted into the corresponding 9a-fluorollfi-hydroxycompound. Starting from compounds wherein Z is CH(l -O R12) the same a-compound can 12 be prepared via dehydration of starting materialswherein R and R are both hydrogen, using for example, thionyl chloridein pyridine. These various methods of modifying the 9- and ll-positionare known per se, and the known techniques are applicable to thecompounds of this invention.

The compounds of this invention are characterized by a high degree ofendocrinological usefulness with a selectivity of action characterizedby minimal side effects. Thus, the endocrinologically useful compoundsof this invention, i.e., those of partial and complete Formulas I-IV andX indicated to be endocrinologically useful above, can be administeredinternally, for example, orally or parenterally, with dosage adjusted toindividual requirements, in the form of conventional pharmaceuticalpreparations; for example, they can be administered in conventionalpharmaceutical solid or liquid forms, such as, tablets, pills, capsules,solutions, suspensions, emulsions, or the like. These pharmaceuticalpreparations can contain conventional pharmaceutical carriers andexcipients, such as, water, talc, corn starch, polyalkylene glycols,emulsifying agents, buffering agents, agents for the adjustment ofosmotic pressure, Vaseline, and the like. Though it is preferred toadminister the endocrinologically useful compounds of this inventioninternally, the endocrinologically useful compounds of this inventionhaving progestational, i.e., those of partial Formulas I and II or III,or anti-inflammatory, i.e., those of partial Formulas I and IV,usefulness can also be administered topically. For this purpose, i.e.,topical administration, these compounds can be administered inconventional topical administration forms such as ointments or creams,in combination with conventional topical carriers such as petrolatum,stearic acid or the like. Also compositions containing an activeingredient of this invention can be subjected to conventionalpharmaceutical processes, such as, sterilization or the like. Also, thepharmaceutical compositions of this invention can contain other activeingredients. Moreover, the endocrinologically active compounds can beadministered as feed additives, and for this purpose can be admixed withconventional animal feeds or conventional animal feed premixes. Thoughas indicated dosage of the endocrinologically useful compounds of thisinvention should be adjusted to individual needs, compounds useful asprogestational agents, i.e., those of partial Formulas I and II, can beadministered internally in daily dosage regimens of from about 0.005mg./kg. to about 0.15 mg./kg. per day. Also, compounds useful asandrogenic and anabolic agents, i.e., those of partial Formulas I andIII and of Formula X, can be administered internally in daily dosageregimens of from about 0.15 mg./kg. to about 1.5 mg./kg. per day.Moreover, compounds useful as anti-inflammatory and thymolytic agents,i.e., those of partial Formulas I and IV, can be administered internallyin daily dosage regimens of from about 0.005 mg./kg. to about 0.3 mg./kg. per day. Dosages can be administered in unit or divided dosageforms.

The usefulness of the compounds exhibiting endocrinological activity isindicated in animals, for example, the progestational compounds of thisinvention, when administered to estrogen primed immature female rabbitsfor five days show the presence of progestational activity by asecretory type endometrial response observed on histological sectionsprepared from the rabbits uteri and examined microscopically. A maximalresponse is demonstrated by progesterone at 200 mcg./ day for five days.As exemplary of the progestational compounds of this invention there canbe named l7a-acetoxy-4,6-dichloro-pregna-4,6-diene-3,20-dione;17u-acetoxy-4,6-dichloro-3,3-ethylenedioxy-pregnet-4,6-

diene-20-one; 17a-acetoxy-4,6-dichloro-pregna-1,4,6-triene-3,20-dione;17ot-acetoxy-4,6-dichloro-pregna-4,6-dien-3fl-ol-20-one; 3 p, 17a-diacetoxy-4,6-dichloro-pregna-4,6-diene-20-one;

4,6-dichloro-3B,17a-dihydroxy-16-methylenepregna 4,6-dien-20-one17-acetate; 4,6-dichloro-17a-acetoxy-16-methylenepregna-4,6-dien-3,20-dione; 4,6-dichloro-3/8,17x-diacetoxy-16-methylenepregna-4,6-diene-20-one; 4,6-dichloro-17a-acetoxy-16-methylenepregna-l,4,6-

triene-3,20-dione; 4.,6,7-trichloro-17a-hydroxypregn-5-ene-3,20-dioneacetate; 45,6,7g-trichloro-17a-hydroxy-16-methylenepregn-5-ene-3,20-dione acetate and4,6-dichloro-17fl-hydroxy-19-nor-17a-pregna-4,6-diene- 20-yn-3-one,

which when examined in two rabbits each showed progestational activityat 10 mcg./kg./day s.c. or less. Mineralocorticoid activity is shown bya procedure wherein male bilaterally adrenalectomized rats weighingapproximately 125-150 g. are fasted and deprived of drinking waterovernight. In the morning the animals are weighed and then injected witha compound at 50 mg./tkg. s.c. and 5 ml./ 100 g. of 0.9% sodium chlorides.c. at a separate site. There is a control group getting vehicle andsaline load only. After injection the animals are placed in metabolismcages and their urine is collected for six hours. The urine is thenanalyzed for sodium and potassium content by a flame photometer. Theresults are expressed as percent difierence of sodium and potassiumexcretion from controls. In this procedure desoxycorticosterone acetateat 0.25 mg./kg. gives an average sodium difference of -50 to 60%.Glucocorticoid activity is shown by a procedure wherein male ratsweighing 50-60 g. each are bilaterally adrenalectomized and injected ata dose of 2.5 mg./rat/day s.c. for three consecutive days with thecompound suspended in an aqueous suspending vehicle. Injections arebegun on the day of adrenalectomy and the animals are autopsied on thefourth day. Thymus weight is determined and compared to that of thecontrol animals which received the suspending vehicle alone. In thisprocedure hydrocortisone at 0.5 mg./ day gave about a 58% change inthymus weight as compared to controls. Illustrative of the compounds ofthis invention are 4,6-dichloro-17a,21-dihydroxypregna 4,6 dim-3,11,20-trione 21-acetate and4-chloro-6-fluoro-17,2l-diyhydroxypregna-4,6-diene-3,11,20-trione21-acetate which in this procedure are more than twice as potent ascortisone. Androgenic and/or anabolic activity is shown in a pro cedurewherein five castrated rats weighing approximately 40-50 g. each aregiven subcutaneous injections of the compound suspended in sesame oil,whereas a control group of five rats is administered the sesame oilvehicle only. After seven days of treatment all animals are autopsiedand weights of their prostates and levator ani muscles are determined.The weight of their levator ani as compared to the control group of ratsis the criterion used for determining anabolic activity. Tetosteronepropionate at 0.1 mg./day gives approximately a 111% increase in thelevator ani muscle weight as compared to the control group. In thisprocedure, as exemplary of the androgenic/anabolic compounds of thisinvention 4,6- dichloro-17fi-hydroxy-l7a-methyl-androsta 4,6 dien-3- onegives an increase in levator ani weight. Prostate change is thecriterion for androgenic activity. Testosterone propionate at 0.1mg./day gives approximately a 595% increase in the weight of theprostate as compared to the control group.

Besides those described above other of the intermediates useful in thepreparation of the end-products of this invention also areendocrinologically useful, for example,17a-acetoxy-6-chloro-16B-methy1pregna 4,6 diene-3,- 20-dione is usefulas a progestational agent and can be used in the same manner as are theprogestational agents described above.

The following examples are illustrative of this invention but notlimitative thereof. Most of the starting material compounds are knowncompounds or members or known classes of compounds. In any event, thestarting materials can be prepared by known methods as, for example,those in certain instances exemplified in the following examples. Alltemperatures in the examples are stated in degrees centigrade.

Example 1 A solution of 25 g. of17fl-hydroxy-17a-methylandrost-4-ene-3,11-dione in 125 ml. of anhydrouspyridine and 125 ml. of acetic anhydride was heated under reflux for 4hrs. The reaction mixture was then cooled and diluted with 1 liter ofether-methylene chloride mixture (25:1). The organic solution was thenwashed twice with 1 N hydrochloric acid solution, twice with 5% sodiumbicarbonate solution and once with water. The organic layer was dried(Na SO and was then concentrated under reduced pressure. The residue wasthen passed through a short column pf synthetic magnesia-silica gel(Florisil, available from The Floridin Company, Box 989, Tallahassee,Fla.), the product being eluted with benzene. The benzene eluate wasconcentrated under reduced pres sure and the residue was crystallizedfrom ether-hexane giving 17;?acetoxy-17a-methyl-androst-4-ene-3,1l-dione, M.P. 188190, [a] +17O (c.1.0 in CHCl A slow stream of hydrogen chloride was bubbled for about 10seconds through a solution of 10.0 g. of17,8-acetoxy-17a-methyl-androst-4-ene-3,1l-dione in 150 ml. of anhydrousdioxane. In a separate flask, a slow stream of anhydrous hydrogenchloride was bubbled for about 10 seconds through a solution of 6.95 g.of 2,3-dichloro-5,6- dicyanobenzoquinone in 130 ml. of anhydrousdioxane. The two dioxane solutions were then mixed together and hydrogenchloride was bubbled through the so-formed mixture for about seconds.The reaction mixture was then allowed to stand at room temperature for35 minutes, and was then filtered from the resulting precipitate.

The filtrate was concentrated to about 50 ml. under reduced pressure andwas then diluted with 1 liter of ethermethylene chloride mixture (2.5:1). The organic solution was separated, washed twice with dilute sodiumhydroxide (1 N) solution and once with water. The organic layer wasdried (Na SO and evaporated under reduced pressure. The residue wasfiltered through a short column of synthetic magnesia-silica gel(Florisil, available from The Floridin Company, Box 989, Tallahassee,Fla.), the product, 17B-acetoxy-17a-methyl-androsta-4,6-diene-3,11-dione, being eluated with benzene and ethyl acetate. The eluates werecombined and evaporated. The residue was crystallized from methylenechloride-ether giving 17 3- acetoxy-17u-methyl-androsta 4,6 diene 3,11dione, M.P. 182-184, [a] l-226 (c. 1.0 in CHCl Example 2 To a solutionof 4.7 g. of 17 8-acetoxy-17a-methylandrosta-4,6-diene-3,1l-dione in 940ml. of methylene chloride and 225 ml. of ether was added 125 ml. of a0.8 molar solution of mono-perphthalic acid in ether. The reactionmixture was allowed to stand at room temperature for 41 hrs. and wasthen diluted with 1.4 liters of ether. The organic layer was separated,washed twice with 10% sodium carbonate solution, twice with water andtwice with brine. The organic layer was dried (Na SO and was thenconcentrated under reduced pressure. The residue was crystallized frommethylene chloride-ether giving crude product, 17,6 acetoxy17a-methyl-6a,7a-epoxyandrost-4-ene-3,11-dione which upon furthercrystallization from methylene chloride-ether melted at 233.5237, [a]+142 (c. 0.75 in CHCl 'Example 3 Hydrogen chloride was bubbled for 10minutes through a solution (room temperature) of 2.34 g. of Nil-acetoxy-17oz methyl 6u,7u epoxy-androst-4-ene-3,11-dione in ml. of glacialacetic acid. The solution was then 15 allowed to stand at roomtemperature for an additional 3 hr., and was then diluted with 700 ml.of cold water. The resulting mixture was then extracted three times withether-methylene chloride mixture (2.5 :1). The organic layers werewashed twice with 5% sodium bicarbonate solution, once with water andonce with brine. The combined organic layers were dried (Na SO andconcentrated under reduced pressure. The residue was chromatographed on30 g. of synthetic magnesia-silica gel (Florisil, available from The'Floridin Company, Box 989, Tallahassee, Fla.). The column was elutedwith benzene-ethyl acetate and the resulting product was crystallizedfrom methylene chloride-ether giving 17;3 acetoxy 6chloro-17a-methyl-androsta-4,6-diene,3,11- dione which uponcrystallization from ether-hexane melted at 137.3-139", [u] +2O9 (c.0.71 in CHClg).

Example 4 To a cooled solution of 2.03 g. of 17a-acetoxy-6chloro-pregna-4,6-diene-3,20-dione in 20 ml. of dimethylformamide and 10ml. of ether was added 5.39 ml. of a 1.015 M solution of chlorine inpropionic acid. The mixture was allowed to stand at 0 for 12 hourswhereupon an additional 0.3 ml. of the chlorine solution was added andthe mixture was then allowed to stand for an additional 2 hours at 0".

The reaction mixture was then poured into 300 ml. of Water and theresulting mixture was extracted three times with ethermethylene chloridemixture (2.5:1). The organic layers were washed once with sodiumbicarbonate solution and once with brine. The combined organic layerswere then dried (Na SO and evaporated under reduced pressure. Theresidual oil was triturated in the presence of ethyl acetate givingcrude l7u-acetoxy-4,6- dichloro-pregna-4,6-diene-3,20-dione which uponfurther crystallization from chloroform-ethyl acetate formed colorlesscrystals of 17a-acetoxy-4,6-dichloro-pregna-4,6- diene-3,20-dione, M.P.237239.5, [oc] +135 (c. 1.03 in CHCl According to the above procedure,chlorination of:

(a) 21 acetoxy-llfi,17a-dihydroxy-6-chloro-pregna-4,6- diene 3,20-dioneyields 2l-acetoxy-l1B,17a-dihydroxy-4,6-dichloro-pregna-4,6-diene-3,20-dione.

( b) 21 -acetoxy 1118,170; dihydroxy-6,9a-difiuoro-16amethylpregna-4,6-diene-3,20-dione yields 21-acetoxy- 116,170:dihydroxy-4-chloro-6,9a-difluoro-lGot-methylpregna-4,6-diene-3,20 dione.

Example 5 To a cold (0) solution of 1.0160 g. of6-chloro-17aacetoxypregna-4,6-diene-3,20-dione in 10 ml. of alcohol freechloroform was rapidly added (at 0") 3.4 ml. of a 0.817 M solution of C1in dry carbon tetrachloride. This solution was stored at 0 for 18 hrs.The solvent was then removed under reduced pressure and the residue wastreated with 25 ml. of heptane and the solvent was again removed underreduced pressure. This operation was repeated a second time. The residuewas then treated with 4 ml. of dry pyridine and the resulting solutionwas heated on a steam bath for 5 minutes. The solution was then allowedto stand at room temperature overnight (pyridine hydrochlorideprecipitated from the reaction mixture). To the pyridine solution wasthen added 50 ml. of chloroform and the resulting solution was twiceextracated, each time with 50 ml. of 1 N hydrochloric acid. The aqueouslayer was then extracted with 25 ml. of ether. The organic layers werecombined, dried over magnesium sulfate and evaporated under reducedpressure. The residue was treated with 25 ml. of heptane which wasevaporated under reduced pressure. This operation was repeated asecondtime giving crude 4,6-dichloro-17a-acetoxy-pregna-4,6-diene-3,20-dione which was recrystallized twice from methylenechloride-ethylacetate yielding crystals, M.P. 241-243 Example 6 To acooled (2) solution of 6-chloro-l7a,21-dihydroxy-pregna4,6-diene-3,11,20-trione 21-acetate in 16 ml. of dry dimethylformamideand 10 ml. of ether was added 4.0 ml. of a 1.05 M solution of chlorinein propionic acid. The reaction mixture was allowed to stand at 2 for 10hours and then at room temperature for 5 hours. The reaction mixture wasthen poured into ml. of water and was extracted with methylene chloride.The organic layer was washed twice with 5% sodium bicarbonate solutionand once with brine. The organic solution was then dried over sodiumsulfate and evaporated. The residue was crystallized three times frommethylene chloride-ether giving4,6-dichloro-l7u,2l-dihydroxypregna-4,6-dien3,11,20-trione 21-acetate,M.P. 257.5259.5, [a] +398.4 (c. 0.51 in CHCl Example 7 To a cooled (0)solution of 0.60 g. of l7fi-acetoxy-6-chloro-l7a-methyl-androsta-4,6-diene-3,1l-dione in 6 ml. ofdimethylformamide and 3 ml. of ether was added 2.0 ml. of a 0.98 Msolution of chlorine in propionic acid. The reaction mixture was allowedto stand at 0 for 12 hours. The reaction mixture was then diluted with100 ml. of water and the resulting mixture was extracted three timeswith ether-methylene chloride mixture (2.511). The organic layers werewashed once with 5% sodium bicarbonate solution and once with brine. Thecombined organic layers were dried (Na SO and evaporated to drynessunder reduced pressure. The residual oil was triturated withether-hexane giving crude 17B-acetoxy-4,6- dichloro 17cc methyl-androsta4,6 diene-3,1l-dione which upon further crystallization from methylenechloride-ether formed colorless crystals of 17B-acetoxy-4,6- dichloro17ot-methyl-androsta-4,6-diene-3,ll-dione, M.P. 209-211", [a] +34l.5 (c.0.523 in CHCl According to the above procedure, chlorination of:

(a) l7fl-acetoxy-6-chloro-17a-methyl-androsta-4,6-dien- 3-0ne yields17fi-acetoxy4,6-dichloro-17a-methylandrosta-4,6-diene-3-one.

(b) 17a-ethynyl-6-chl0ro- 17 B-hydroxy- 1 9-nor-androsta- 4,6-dien-3-oneyields17a-ethynyl-4,6-dichloro-17B-hydroxy-19-nor-androsta-4,6-dien-3-one.

(c) 17fl-acetoxy-17a-methyl-6-chloro-19-nor-androsta- 4,6-dien-3-oneyields17,8-acetoxy-17a-methyl-4,6-dichloro-19-nor-androsta4,6-dien-3-one.

Example 8 To a cooled (10) solution of 2.0 g. of 17a-acetoxy-6-methy-pregna-4,6-diene-3,20-dione in 21 ml. of dimethylformamide and10.5 ml. of ether was added 5.0 ml. of a 1.15 M solution of chlorine inpropionic acid. The reaction mixture was then allowed to stand at 0 for6 hours and then at 20 for 14 hours. The resulting mixture was pouredinto 200 ml. of water and was extracted three times with ether-methylenechloride mixture (2.5: 1). The organic layers were washed once with 5%sodium bicarbonate solution and once with brine. The combined organiclayers were dried (Na SO and evaporated under reduced pressure. Theresidue was crystallized twice from methylene chloride-ether givingacetoxy-4-chloro-6- methyl-pregna 4,6-diene-3,20-dione which uponfurther purification by crystallization from methylene chlorideethermelted at 217.5-218.7.

Example 9 A solution of 0.439 g. of4,6-dichloro-17a-acetoxypregna-4,6-diene-3,20-dione, 0.03 g. ofp-toluenesulfonic acid and 2.5 ml. of ethylene glycol in 15 ml. of drybenzene was distilled slowly over a 1.5 hour period. An additional 0.8ml. of ethylene glycol, 8 ml. of benzene and 0.005 g. ofp-toluenesulfonic acid was then added and slow distillation was carriedout for an additional two hours. The cooled reaction mixture was thendiluted with 20 ml. of

17 ether and 40 ml. of sodium bicarbonate solution. The two phases wereseparated and the organic layer was washed once with 5% sodiumbicarbonate solution and once with water. The organic layer was driedover sodium sulfate, concentrated and the residue crystallized on theaddition of ether. The resulting solid was crystallized twice frommethylene chloride-ether mixture giving 3- cyclic ethylene acetal of4,6-dichloro-l7a-acetoxypregna- 4,6-diene-3,20-dione, M.P. 266.5-268",[a] +78.l6 (c. 0.99 in CHCl Example 10 To a cooled (0) solution of 0.698g. of 6-fiuoro-17,2ldihydroxypregna-4,6-diene-3,l1,20-trione ZI-acetatein 10 ml. of alcohol-free chloroform was added 2.93 ml. of a 0.813 molarsolution of chlorine in dry carbon tetrachloride. The reaction mixturewas allowed to stand at 0 for 18 hours. The solvent was then removedunder reduced pressure and the residue was treated with 25 ml. ofheptane. The solvent was again removed under reduced pressure and thesolid residue was dissolved in 2 ml. of dry pyridine. After 24 hours atroom temperature the pyridine solution was treated with 25 ml. of l Nhydrochloric acid and the product was extracted with chloroform. Thechloroform solution was then washed twice, each time with 10 ml. of 1 Nhydrochloric acid and the combined aqueous layers were extracted with 50ml. of ether. The organic layers were combined and dried over magnesiumsulfate. The solvent was removed under reduced pressure and the residuewas crystallized from methylene chloride-ethyl acetate yielding4-chloro-6-fluoro 17,21-dihydroxypregna-4,6-diene-3,11,20-trione 21-acetate, M.P. 245-247 (sinters 226). Evaporation of the mother liquorand recrystallization of the residue yielded further product.

Example 11 To a stirred suspension of 1.0 g. of4,6-dichloro-17ahydroxypregna-4,6-diene-3,20-dione in 15 ml. of hexanoicacid was added 4.0 ml. of trifiuoroacetic anhydride. The solid rapidlywent into solution and stirring was continued at room temperature for 16hours. The reaction mixture was then poured into 100 ml. of cold 5%sodium bicarbonate solution and the resulting mixture was extractedthree times with ether-methylene chloride mixture (2.5 :1). The organiclayers were washed twice with 0.5 N sodium hydroxide solution, once withbrine and were then combined, dried over sodium sulfate and evaporated.

The residue was dissolved in benzene-hexane (2:1) and was thenchromatographed on 15 g. of synthetic magesiasilica gel (Florisil,available from The Floridin Company, Box 989, Tallahasse, Fla). Theproduct was eluted with benzene, 30% ethyl acetate-benzene and finallywith ethyl acetate. The eluents were evaporated and the residues werecrystallized by trituration with ether. The resulting solids werecombined and crystallized from methylene chloride-ether giving crystalsof 4,6-dichloro-l7a-hydroxypregna 4,6-diene-3,20-dione caproate, whichupon one further crystallization from the same solvent system formedcrystals, M.P. ll8.5l, [a] +1l5.56 (c. 0.98 in CHCl Example 12 To acooled (0) solution of 0.60 g. of l7fi-acetoxy-6-chloro-17a-methyl-androsta-4,6-diene-3,1l-dione in 6 ml. of drydimethylformamide and 3 ml. of ether was added 2.0 ml. of a 0.98 Msolution of chlorine in propionic acid. The reaction mixture was allowedto stand at 0 for 3 hours. The reaction mixture was then diluted with100 ml. of water and the resulting mixture extracted three times withether-methylene chloride mixture (2.5 :1). The organic layers werewashed once with 5% sodium bicarbonate solution and once with brine. Thecombined organic layers were dried (Na SO and evaporated to drynessunder reduced pressure. The residual oil was dissolved in benzene andchromatographed on a 5 g. column of synthetic magnesia-silica gel(Florisil, available from The Floridin Company, Box 989, Tallahassee,Fla.). The benzene and ethyl acetate eluates were combined andevaporated to dryness. To a cooled (0) solution of the residue in 6 ml.of dry dimethylformamide and 3 ml. of ether was added 2 ml. of a 0.05 Msolution of chlorine in propionic acid. The reaction mixture was allowedto stand at 0 for 12 hours and was then diluted with ml. of water. Themixture was extracted three times with ether-methylene chloride mixture(25:1) and the organic layers were washed once with 5% sodiumbicarbonate solution and once with brine. The combined organic layerswere dried (Na SO and evaporated to dryness under reduced pressure. Theresidue crystallized on trituration with ether-hexane giving crudeflit-acetoxy- 4,6-dichloro-17a-methylandrosta 4,6 diene-3,11-dione whichupon further crystallization from methylene chloride-ether formedcolorless crystals, M.P. 209-211", [a] +341.5 (c. 0.52 in CHCl Example13 To a solution of 5.0 g. of 6-chloropregna-4,6-diene- 3,20-dione in 30ml. of dichloromethane and 250 ml. of ether cooled to 10 and protectedfrom atmospheric moisture was added 15.8 ml. of a 1.1 M chlorine inpropionic acid solution. The solutions were mixed thoroughl and allowedto stand at 0 overnight. Benzene (100 ml.) was added and the solutionwas concentrated under vacuum to about 200 ml. Pyridine (83 ml.) wasthen added and the resultant solution was heated at 40 for 5 hr. andpoured into water. The organic layer and an ether extract of the aqueouslayer were combined and Washed with water, 2 N hydrochloric acid, water,5% sodium bicarbonate and finally with water, dried over sodium sulfateand evaporated. The residue was dissolved in 20% benzene in hexane andadsorbed onto g. of silica gel. Early benzene fractions eluted some lesspolar material and later benzene fractions eluted crystalline product.These crystalline fractions were combined and crystallized from ethanoland hexane giving 4,6-dichloro-pregna-4,6-diene-3,20-dione as colorlesscrystals which upon one further recrystallization gave crystals, M.P.127-130",

Example 14 A solution of 1.00 g. of 4,6-dichloro-pregna-4,6-diene-3,20-dione in 10 ml. of carbon tetrachloride protected from atmosphericmoisture is cooled to 10 and a mixture of 0.1 ml. of 70% perchloric acidand 2 ml. of acetic anhydride is added over 10 minutes. After stirringfor an additional hour at 10, the solution is diluted with 100 ml. ofether and washed with 5% sodium bicarbonate and then with water. Thesolution is dried over sodium sulfate and concentrated to an oilcontaining 20acetoxy-4,6- dichloropregna-4,6,17(20)-triene-3-onesufiiciently pure for subsequent reactions.

Example 15 To a stirred solution of 20-acetoxy-4,6-dichloropregna-4,6,l7(20)-triene-3-one (prepared from 0.50 g. of 4,6-dichloropregna-4,6-diene-3,20-dione according to the procedure ofExample 14) in 2.5 ml. of benzene is added 0.5 ml. of 40% peraceticacid. After 4 days, 5 ml. of 10% sodium sulfite is added and the mixtureis stirred vigorously. The reaction mixture is diluted with ether,washed with water, dried (Na S0 and evaporated. The residue is adsorbedonto silica gel from benzene solution and eluted with 5% ether inbenzene. Crystallization from ether gives 17a-hydroxy 4,6dichloropregna-4,6-diene- 3,20-dione.

Example 16 A solution of 20 acetoxy 4,6 dichloropregna-4,6,

17(20)-triene-3-one (prepared from 0.50 g. of4,6-dichloropregna-4,6-diene-3,20-dione according to the procedure ofExample 14) in 8.0 ml. of benzene is added with stirring over minutes toa mixture of 2.0 ml. of 40% peracetic acid and 80 mg. of sodium acetate.After the reaction mixture has been stirred at room temperature for 13hours, ml. of ice water followed by ml. of 10% sodium sulfite is added.The organic layer is then diluted with ether, washed with water, dried(Na SO and evaporated to an oil containing 20-acetoxy-l7a,20-oxido-4,6-dichloropregna-4,6-diene-3-one sufliciently pure forsubsequent reactions.

Example 17 A mixture of 20 acetoxy-17a,20-oxido-4,6-dichloropregna-4,6-diene-3-one (prepared from 0.25 g. of 20-acetoxy 4,6dichloropregna-4,6,l7(20)-triene-3-one according to the procedure ofExample 16), 20 ml. of methanol and 300 mg. of sodium carbonatemonohydrate is stirred at room temperature for 2 hours. Ice water ml.)is added and after stirring for an additional minutes the resultantsolid is collected. Recrystallization from ether gives 17a-hydroxy 4,6dichloropregna-4,6- diene-3,20-dione.

Example 19 An ointment of the following formulation is prepared asdescribed below:

' Per kilo g. White petrolatum, U.S.P. 999 4,6 dichloro 17aacetoxypregna-4,6-diene-3,20-

dione 1 The white petrolatum U.S.P. was placed in a suitable jacketedmixing kettle and heated to approximately 85 with constant slowagitation. The drug,4,6-dichloro-l7aacetoxy-pregna-4,6-diene-3,20-dione, which was firstground to a fine powder in a small ball mill, was then added slowly tothe melted petrolatum and the mixture stirred until thoroughly mixed.Cool water was then circulated through the jacketed kettle and thecooling continued until the temperature reached about 36. The mixturewas then passed into an Eppenbach colloid mill at a setting of 20microns. The so-obtained preparation was then packaged in opal glassjars. If desired, aluminum or tin ointment tubes can be substituted forthe glass jar.

Example 20 Capsules containing the following formulation are prepared asdescribed below:

Per capsule mg. 4,6 dichloro 17cc acetoxypregna 4,6 diene- 3,20-dione0.5 Lactose 180.0 Corn starch 39.5 Talc 5.0

Total weight 225.0

20 then returned to the mixer, the talc added and the resultant mixtureblended thoroughly. It was then filled into No. 4 hard shell gelatincapsules on a casulating machine.

Example 21 Tablets of the following formulation are prepared asdescribed below:

Per tablet mg. 4,6 dichloro 17o: acetoxypregna 4,6 diene- 3,20-dione 1.0Lactose, spray dried 95.0 Corn starch, U.S.P. 3.0 Calcium stearate 1.0

Total weight 100.0

The 4,6-dichloro-17a-acetoxypregna 4,6-diene-3,20- dione, lactose, cornstarch and calcium stearate were blended in a suitable mixer. The powderwas then compressed on a heavy duty tablet compressing machine andyielded tablet slugs of about 1'' diameter and A" thickness. The tabletslugs were passed through a suitable comminuting machine and yieldedgranules of approximately 16 mesh with a minimum of fines. Thegranulation was recompressed on a tablet compressing machine using a A"standard concave punch to an average tablet weight of mg.

Example 22 A 12 /2 premix for animal feed of the following compositionis prepared as described below:

Grams/kilo gms. 4,6 dichloro 17a acetoxypregna 4,6 diene- 3,20-dioneCorn germ meal 831 Drew oil 1400 1 44 Total weight 1000 Drew 011 1400 isa mixture of glyeeryl trlesters of lower molecular (Ca-C1 weight fattyacids (available as Drew Oil 1400, E. F. Drew 8a (30., Inc., New York,N.Y. Also, this type of oil is described in B'arsky et 11., U.S.P.2,988,484).

The corn germ meal was placed in a suitable mixer and while mixing, theDrew Oil 1400 was slowly added and thoroughly mixed. While mixingcontinuously the 4,6-dichloro-17a-acetoxypregna-4,6 diene 3,20 dione wasslowly added and mixed until the mixture was homogenous. This premix wasthen added to a commercial poultry feed at the ratio of 2 lbs/ton toyield a ratio of 0.0125 drug, and thoroughly mixed. This medicated feedwas used in the mash form, and it was also pelleted on a pellet mill,the Sprout-Waldron Pellet Mill.

Amounts of the above premix can be added to the commercial feed to yieldmedicated levels ranging from 0.005% to 0.05%. The commercial feeds towhich this premix is added can be free of other medicaments or cancontain other medicaments.

Example 23 A 6% premix for animal feed of the following composition isprepared as described below:

Grams/kilo gms. 4,6 dichloro 17a acetoxypregna 4,6 diene- 3,20-dione 60Corn germ meal 896 Drew Oil 1400 1 44 Total weight 1000 and thoroughlymixed. While mixing continuously the 4,6-dichloro17a-acetoxypregna 4,6diene 3,20 dione was slowly added and mixed until the mixture washomogenous. This premix was then added to a commercial poultry feed atthe ratio of 2 lbs/ton to yield a ratio of .006% drug, and thoroughlymixed. This medicated feed was used in the mash form, and it was alsopelleted on a pellet mill, the Sprout-Waldron Pellet Mill.

Amounts of the above premix can be added to the commercial feed to yieldmedicated levels ranging from 0.0005 to 0.05%. The commercial feeds towhich this premix is added can be free of other medicaments or cancontain other medicaments.

Example 24 A cream of the following formulation is prepared as describedbelow:

Percent 4,6 dichloro 17a acetoxypregna 4,6 diene- 3,20-dione 0.1 Stearicacid 13.50 Light mineral oil 1.35 Sorbitan monostearate 2.25 Methylp-hydroxybenzoate 0.08 Propyl p-hydroxybenzoate 0.02 Sorbitol 4.50Polysorbate 60 (i.e., polyoxyethylene 20 sorbitan 1 60 monostearate)Distilled water q.s. ad 100.00. pH (approx) 5.1.

Example 25 A liquid concentrate of the following formulation is preparedas described below:

Per kilo g.

4,6 dichloro 17a acetoxypregna 4,6-diene 3,20-

dione 25 Polysorbate 80, U.S.P (i.e., polyoxyethylene 20 sorbitanmonooleate) 400 Propylene glycol 575 The polysorbate and propyleneglycol were well mixed in a suitable size glass container, and the drug,4,6-dichloro-17a-acetoxypregna-4,6-diene-3,20-dione, was slowly addedwith constant stirring. This 2.5 concentrate of the drug was packaged ina glass container for shipment and storage. In use the 2.5% concentrateis diluted by addition to a molasses based liquid protein supplement togive a concentration of from one to ten mg. of drug per pound of liquidprotein supplement. This is then added to the final grain carrier inamounts sufficient to give the desired dosage of drug per day peranimal.

Example 26 To a stirred solution of 10.0 g. of 3-eth0Xy-17B-acetoXy-17a-methyl-androsta-3,S-diene in 500 ml. of acetone was added a solutionof 6.0 g. of sodium acetate in 60 ml. of water. The resulting mixturewas cooled to 5 and 4.3 g. of N-chlorosuccinimide was added over a 5minute period, followed by the rapid addition of 33.6 ml. of glacialacetic acid. The reaction mixture was then allowed to stir at 5 for 75minutes and was then diluted with 750 ml. of water. The mixture wasextracted 3 times each time with ether-methylene chloride mixture(25:1). The organic layers were washed once with 5% sodium bicarbonate22 solution and once with water. The combined organic layers were driedover sodium sulfate and evaporated. The residue was dissolved in benzeneand chromatographed on a 300 g. column of synthetic magnesia-silica gel(Florisil, available from The Floridin Company, Box 989, Tallahassee,Fla.). The benzene and ethyl acetate eluents were combined andevaporated. The residue was crystallized from acetone-hexane giving6fl-chloro-17p-acetoxy-17amethylandrost-4-en3-one, M.P. 155-l58, whichis sufficiently pure for the next step.

Example 27 To a stirred solution of 4.5 g. of 6fl-chloro-17B-acetoxy-17a-methylandrost-4-en-3-one in 25 ml. of dry dioxane was added 5.0 ml.of trimethyl-orthoformate and 0.20 g. of p-toluenesulfonic acid. Thereaction mixture was stirred at room temperature for minutes and wasthen diluted with a solution comprising 50 ml. of water and 2 ml. ofpyridine. The mixture was then stirred at room temperature for 50minutes and the resulting precipitate was then filtered, washed withwater and crystallized from acetone (about 20 ml., containing 1 ml. ofpyridine) giving 6- chloro 3methoxy-17/3-acetoxy-17u-methylandrosta-3,5- diene, M.P. 133-1355".

Example 28 To a stirred solution of 81 g. of 6-chloro-3-methoxy-17B-acetoxy-17a-methylandrosta-3,5-diene in 2.4 liters of carbontetrachloride was added 810 ml. of a solution of t-butyl chromate,prepared by the method of K. Heusler and A. Wettstein, Helv. Chim, Acta,35, 289 (1952), in carbon tetrachloride, followed by 81 ml. of aceticanhydride. The resulting mixture was heated under reflux for 12 hours. Asolution of 243 g. of oxalic acid in 2 liters of water was then added tothe cooled solution, and an exothermic reaction occurred while themixture was stirred for 2 hours. The cooled reaction mixture was thenextracted with 3 liters of chloroform and the organic layer wasseparated and washed once with water, once with 5% sodium carbonatesolution (1 liter) and once with brine. The organic layer was dried oversodium sulfate and evaporated. The residue was dissolved in benzene andchromatographed on 1 kg. of synthetic magnesiasilica gel (Florisil,available from The Floridin Company, Box 989, Tallahassee, Fla.). Theproduct was eluted with 4.5 liters of 10% ethyl acetate-benzene, and 1.5liters of 20% ethyl acetate-benzene. The combined fractions wereevaporated and the residue was crystallized from ethyl acetate giving 6chloro-17,8-acetoxy-l7-methylandrosta-4,6-dien-3-one, which uponcrystallization from ethyl acetate melted at 161-1625, [a] |25.80. (C.0.53 in CHCL Example 29 To a cooled (0) solution of 1.5 g. of6-chloro-17flacetoxy-17a-methylandrosta-4,6-dien-3-one in 15 ml. of drydimethylformamide and 10 ml. of ether was added 3.2 ml. of 1.4 Msolution of chlorine in propionic acid. The mixture was allowed to standat 0 for 24 hours and then at 25 for 12 hours.

The reaction mixture was then poured into ml. of cold water and theresulting mixture was extracted three times with ether-methylenechloride mixture (2.511). The organic layers were washed once with 5%sodium bicarbonate solution and once with brine. The combined organiclayers were dried over sodium sulfate and evaporated under reducedpressure. The residue was dissolved in benzene and chromatographed on 15g. of synthetic magnesia-silica gel (Florisil, available from TheFloridin Company, Box 989, Tallahassee, Fla.). The benzene and ethylacetate eluates were evaporated and the residue was crystallized oncefrom methylene chloride-ether and three times from methanol giving4,6-dichloro-l7fi-acetoxy-17mmethylandrosta-4,6-dien-3-one, M.P.14l-146, [a] 158.9" (c. 0.53 in CHCl 23 Example 30 To a stirred solutionof 20.0 g. of lithium aluminum hydride in 1 liter of ether was rapidlyadded a solution of 25.0 g. of6-chloro-1713-acet0xy-17-methylandrosta-4,6-dien-3-one in 2 liters ofether. The reaction mixture was stirred at 0 For 10 minutes and was thenallowed to warm to room temperature over a 1 hour period. The mixturewas then again cooled to 0 after which 100 ml. of ethyl acetate wasadded over a 10 minute period, followed by the addition of 250 ml. ofsaturated sodium sulfate solution. The reaction mixture was warmed toroom temperature and filtered through a bed of filter aid. Theprecipitate was washed with ether and methylene chloride. The filtratewas washed with water, dried over sodium sulfate and evaporated to givea colorless solid which was dissolved in 250 ml. of dry dioxane. To theso-formed solution, with stirring, was added a suspension of 20' g. of2,3-dichloro-5,6-dicyanobenzoquinone in 210 ml. of dry dioxane and theresulting mixture was stirred at room temperature for 16 hours. Theresultant precipitate was then filtered, washed with dioxane, and thefiltrate was evaporated to dryness. The residue was dissolved in 1 literof ethermethylene chloride mixture (2.5 :1) and was washed 3 times with1% sodium hydroxide solution (3 liters). The organic layers werecombined, dried over sodium sulfate and evaporated. The residue wasdissolved in benzene and chromatographed on 200 g. of syntheticmagnesia-silica gel (Florisil, available from The Floridin Company, Box989, Tallahassee, Fla.). The columnwas eluted with benzene, 500 ml. of20% ethyl acetate-benzene and 250 ml. of 50% ethyl acetate-benzene. Theeluents were combined and evaporated. The residue was crystallized frommethylene chloride-ethanol giving 6-chloro-173-hydroxy-l7-methylandrosta-4,6-dien-3-one. Additional6-chloro-17fl-hydroxy- 17a-methylandrosta-4,6-dien-3-one was recoveredfrom the mother liquors. Upon recrystallization from ethanol 6 chloro-l73-hydroxy-l7-methylandrosta-4,6-dien-3-one melted at 166-1675 Example 31To a cooled (2) solution of 1.57 g. of 6-chloro-17fl-hydroxy-17a-methylandrosta-4,6-dien-3-one in 15 ml. of drydimethylformamide and 10 ml. of ether was added 6.0 ml. of 0.90 Msolution of chlorine in propionic acid. The mixture was allowed to standat 0 for 12 hours and at 25 for hours.

The reaction mixture was then poured into 100 ml. of water and wasextracted three times with ether-methylene chloride mixture (2.5 1 Theorganic layers were washed twice with 5% sodium bicarbonate solution andonce with brine. The organic layers were then combined, dried oversodium sulfate and evaporated. The residue was crystallized three timesfrom methylene chloride-ether giving4,6-dichloro-17p-hydroxy-17-methylandrosta-4,6-dien- 3-one which uponfurther crystallization from the same solvent system melted at 156-1575,+167.6 (c. 0.53 in CHCI This compound occasionally crystallized as apolymorphic mixture, M.P. 157-181.

Example 32 To a stirred solution of 4.5 g. of4,6-dichloro-17B-hydroxy-17u-methylandrosta-4,6-dien-3-one in 110 ml. ofdry t-amyl alcohol was added 10.5 g. of selenious acid and 4.5 ml. ofacetic anhydride and the resulting mixture was heated under reflux. Anadditional 4.0 g. of selenious acid was added over a 48 hour period.After heating under reflux for a total of '60 hours, the reactionmixture was cooled, diluted with chloroform and filtered. The filtratewas washed once with 5% sodium bicarbonate solution, once with 1 Nhydrochloric acid solution and once with water. The organic layer wasdried over sodium sulfate and evaporated. The residue in benzene waschromatographed on a 50 g. column of synthetic magnesiasilica gel(Florisil, available from The Floridin Com- 24 pany, Box 989,Tallahassee, Fla). The column was eluted with benzene and 30% ethylacetate-benzene. The combined eluents were then evaporated and theresidue was crystallized from methylene chloride-ether giving4,6-dichloro-17fl-hydroxy-17-methylandrosta-1,4,6-trien-3 one which uponfurther crystallization from the same solvent system melted at225-2265", +6.4 (c. 1.06 in CHCl Example 33 To a cooled (-8) solution of87.0 g. of 6-chl0ro-17ahydroxypregna-4,6-diene-3,20-dione in a mixtureof 870 ml. of dimethylformamide (dried over calcium hydride) and 435 ml.of ether was added 356 ml. of a 0.95 M solution of chlorine in propionicacid. The mixture was allowed to stand at 0 for 14 hours and then at 25for 6 hours.

The reaction mixture was then poured into 3 liters of water and wasextracted three times with ether-methylene chloride mixture (2.5 :1).The organic layers were washed twice with 1.5 liters of 5% sodiumbicarbonate solution and once with 2 liters of brine. The combinedorganic layers were dried over sodium sulfate and evaporated underreduced pressure. The residual oil was dissolved in benzene-hexane (2:1)and chromatographed on 1100 g. of synthetic magnesia-silica gel(Florisil, available from The Floridin Company, Box 989, Tallahassee,Fla.). The column was eluted with 2 liters of benzenehexane (0 mg.residue), 1 liter benzene (18 mg), 1 liter 2% ethyl acetate-benzene (32mg.), 1 liter 5% ethyl acetate-benzene (5.92 g.noncrystalline) and 500ml. 10% ethyl acetate-benzene (19.0 g.--n0ncrystalline). Further elutionwith 500 ml. of 10% ethylacetate-benzene (19.3 g.), 1.5 liters of 20%ethyl acetate-benzene (54.1 g.) and 1 liter of 40% ethyl acetate-benzene(16.0 g.) gave fractions which crystallized readily on trituration withether.

The combined solids were crystallized twice from methylenechloride-ether giving4,6-dichloro-17a-hydroxypregna-4,6-diene-3,20-dione which uponcrystallization from the same solvent system melted at 159.5-161", [ch+185.4 (c. 0.5 in CHCl Example 34 To a suspension of 27.0 g. of4,6-dichloro-17a-hydroxypregna-4,6-diene-3,20-dione in 1350 ml. ofglacial acetic acid and 270 ml. of acetic anhydride was added 27.0 g. ofp-toluenesulfonic acid. The reaction mixture was stirred until all solidwent into solution and was then allowed to stand at room temperature fora total of 6 hours.

The mixture was poured into 7 liters of water and after 30 minutes theprecipitate was filtered and washed well with water. The resulting wetproduct was dissolved in about 1 liter of methylene chloride, dried oversodium sulfate and evaporated under reduced pressure to about 200 ml.This solution was transferred to an Erlenmeyer flask and the hotsolution was concentrated with the simultaneous addition of ethylacetate (about ml.). The product precipitated out of the boilingsolution (about 150 ml. final volume) giving4,6-dichloro-l7aacetoxypregna-4,-6-diene-3,20-dione which upon onefurther crystallization from the same solvent system melted at241.5-243". (Additional4,6-dichloro-17a-acetoxypregna-4,6-diene-3,20-dione was obtained fromthe mother liquors).

Example 35 To a solution of 41.4 g. of 3;8,17a-diacetoxy-l618-methylpregn-S-ene-ZO-one in 1130 ml. of dry benzene and 31 ml. ofpyridine was added 0.10 mole of a chlorine in carbon tetrachloridesolution (freshly prepared and standardized). After the reaction wasstirred at room temperature for 1 hour 45 minutes, thin layerchromatography showed the absence of starting material. The reaction wasdiluted with 500 ml. of dichloromethane and washed three times with 1 Nhydrochloric acid and once with water. The organic layer was dried withsodium sulfate and concentrated to a colorless crystalline residue whichon recrystallization from dichloromethane-ether gave3,8,17a-diacetoxy-a,6,8-dichloro 165 methylpre nane-20-one as colorlesscrystals which upon further recrystallization melted at 219-223".

Example 36 A mixture of 30.0 g. of33,17a-diacetoXy-5a,6fi-dichloro-16fl-methylpregnane-20-one, 25.4 g. ofpotassium bicarbonate, 500 ml. of methanol, 600 ml. of acetone and 132ml. of water was refluxed for 4 hours. The reaction mixture was dilutedwith 1 liter of water, cooled to room temperature and filtered giving5a,6B-dichloro-3B,17a-dihydroxy-lGB-methylpregnan-ZO-one 17-acetate ascolorless crystals which upon recrystallization fromdichloromethane-ether melted at 220-2235 Example 37 A solution of 21.0g. of 5a,6/3-dichloro-3;3,17a-dihydroxy-l6l8-methylpregnan-20-one17-acetate in 840 ml. of acetone was cooled to 5 and treated with 8 Nchromic acid solution until a permanent brown color remained (about 25ml.). The reaction mixture was then poured into 7 liters of water,stirred for one hour, and the precipitate was collected by filtrationand washed with water. The damp filter cake was mixed with 19 g. ofsodium acetate and 420 ml. of methanol and heated under reflux for 2hours. The cooled mixture was poured into 4 liters of water and stirredat room temperature. The resulting semisolid precipitate was separatedand dissolved in dichloromethane. This solution was dried with sodiumsulfate and evaporated to give 20 g. ofl7a-acetoxy-6flchloro-16B-methyl-pregn-4-ene-3,20-dione as a viscousoil. An 18 g. portion of this material was mixed with 75 ml. oftetrahydrofuran, 28.4 ml. of triethyl orthoformate and 9.75 ml. ofabsolute ethanol. The resulting solution was covered to protect it fromlight and after the addition of 175 mg. of p-toluenesulfonic acid wasstirred for 90 minutes. The solution was then diluted with 3.6 ml. ofpyridine, followed by 700 ml. of water. The resulting precipitate wascollected by filtration, washed with water and dissolved indichloromethane. This solution was dried with sodium sulfate, andconcentrated to crude 6-chloro-3-ethoxy17a-acetoxy-16B-methylpregna-3,5-diene-20-one as a semisolidresidue (19 g.) which would be used for subsequent reactions.Recrystallization of a portion of this material fromdichloromethane/ether gave 6-chloro-3-ethoxy-17a-acetoxy-16B-methylpregna-3,5-diene-20-one as colorlesscrystals, M.P. 2025-2045".

Example 38 A solution of 10.1 g. of dichlorodicyanobenzoquinone in 44.2ml. of acetone and 2.4 ml. of water was added to a solution of 2.00 g.of crude 6-chloro-3-ethoxy-17aacetoxy-16B-methylpregna-3,S-diene-ZO-onein 176 ml. of acetone and 8.9 ml. of water. The reaction mixture wasstirred for 20 minutes and then concentrated at room temperature. Theresidue was diluted with 1 liter of 1:1 hexanezdichloromethane, washed 3times with 1 N sodium hydroxide, then with water, dried with sodiumsulfate and evaporated to an oil. This was crystallized twice fromdichloromethane-ether giving 6-chloro 17a acetoxy16fimethylpregna4,6-diene-3,20-dione as colorless crystals which uponfurther recrystallization from dichloromethane-methanol melted at257-259".

Example 39 To a solution of 560 mg. of 6-chloro-17u-acetoxy-16B-methylpregna-4,6-diene-3,20-dione in 7 ml. of ether and 3 ml. ofdichloromethane cooled to --30 was added 1.29 mmoles of a chlorine inpropionic acid solution (freshly prepared and standardized). Thesolution was allowed to stand at for 2 hours and then poured into watercontaining excess sodium bisulfite. The aqueous solution was extractedwith dichloromethane and this extract was washed with water, dried andconcentrated to an oil. This was mixed with 5 ml. of pyridine, and afterstanding at room temperature for 2 hours the solution was poured intowater and extracted with a mixture of dichloromethane and ether (2:5).The organic layer was washed with 0.5 N hydrochloric acid, 5% sodiumbicarbonate and water, dried and evaporated to an oil. This wascrystallized from dichloromethane ether giving4,6-diChl0IO-17ocacetoxy-16 8-methylpregna-4,6-diene-3,20-dione ascolorless crystals which upon further recrystallization fromdichloromethane-methanol melted at 243-247.

Example 40 To a solution of 200 mg. of 6-chloro-17B-hydroxy-19-nor-17u-pregna-4,6-diene-20-yn-3-one in 3 ml. of ether and 0.5 ml. ofdichloromethane cooled to 30" was added 0.67 mmole of a chlorine inpropionic acid solution (freshly prepared and standardized). Thesolution was allowed to stand at -15 for 15 minutes and then poured intowater containing excess sodium bisulfite. The aqueous solution wasextracted with dichloromethane and this extract was washed with water,dried and concentrated to an oil. This was dissolved in 2 ml. ofpyridine and after standing at room temperature for 3 days the solutionwas poured into water and extracted with a mixture of dichloromethaneand ether. The organic layer was washed with 0.5 N hydrochloric acid,water, 5% sodium bicarbonate, dried, and evaporated to an oil. This wascrystallized from dichloromethane-ether giving4,6-dichloro-17B-hydroxy-19-nor-17u-pregna-4,6-diene-20-yn-3-one, ascolorless crystals which upon further recrystallization melted at 217dec.

Example 41 A solution of 2.000 g. of17u-acetoxy-4,6-dichloropregna-4,6-diene-3,20-dione in 20 ml. ofanhydrous tetrahydrofuran was added dropwise over a 15-minute period to3.280 g. of lithium aluminum tri-t-butoxyhydride in 20 ml. of anhydroustetrahydrofuran under a nitrogen atmosphere. After stirring at roomtemperature for 2 hours, 20 ml. of acetone was added followed by ml. of10% acetic acid in water. The mixture was extracted with two 75 ml.portions of chloroform, the organic layers were combined, washed with 5%sodium bicarbonate, dried with magnesium sulfate and concentrated underreduced pressure. The crude solid was crystallized from acetonehexanewhich upon recrystallization from the same solvent system yielded17a-acetoxy-4,6-dichloropregna-4,6- dien-3fl-ol-20-one melting at255-257".

Example 42 A mixture of 1.000 g. of 17a-acetoxy-4,6-dichloro-3B-hydroxypregna-4,6-diene-20-one, 10 ml. of acetic anhydride and 10 ml. ofpyridine was left at room temperature for 18 hours. The excess reagentswere removed under vacuum and the residue was diluted with xylene andagain concentrated to dryness. Crystallization from methanol gave318,17a-diacetoxy-4,6-dichloropregna-4,6- diene-20-one which uponrecrystallization from methanol melted at 218220.

Example 43 To 7.48 g. of6,3-chloro-17a,21-dihydroxy-16a-methylpregn-4-ene-3,20-dione 21-acetatein ml. absolute ethanol and 165 ml. absolute dioxane was added 8.25 ml.triethyl orthoformate and 0.578 g. p-toluenesulfonic acid monohydrate.The reaction mixture was stirred at room temperature under a nitrogenatmosphere in the dark for 1 hour, 5.5 ml. of pyridine was added and thesolvents were removed at reduced pressure to yield an oil. The oil wasdissolved in 290 ml. acetic acid and 25 ml. water and 26.4 g. ofactivated manganese dioxide was added in one portion. After stirring for3 hours under a nitrogen atmosphere, the manganese dioxide was removedby filtration through a filter aid and the cake washed well withchloroform. The filtrate was concentrated under vacuum to a viscous oilwhich was taken up in chloroform, washed with 5% sodium bicarbonate,

1 N hydrochloric acid and water. Concentration of the dried (MgSOextract gave a dark residue which was triturated with ether to yield ayellow solid. Chromatography on 80 g. of silica gel and elution with 5%ethyl acetate in benzene gave white solid which was crystallized fromethyl acetate-hexane yielding 6-chloro-17u,21-dihydroxy-l6a-methylpregna4,6-diene-3,20-dione 21-acetate, M.P. 224-227.

Example 44 To 4.178 g. of6-chloro-17a,2l-dihydroxy-16a-methylpregna-4,6-diene-3,20-dione21-acetate in 40 ml. of chloroform (filtered through silica gel toremove alcohol) at 0 was added rapidly 11.0 ml. (0.011 mole; 1.0 molar)of a solution of chlorine in carbon tetrachloride. After 1 hour at 3,the solvents were removed at reduced pressure and the resultant foam wastreated with 25 ml. of pyridine. After standing at room temperature for1 hour 45 minutes, the pyridine was removed on the oil pump and theresidue taken up in methylene chloride, washed with 2 N hydrochloricacid, water, dried with magnesium sulfate and concentrated at reducedpressure. Trituration of the residue with hexane and concentration todryness gave a yellow solid. Chromatography on 125 g. of silica gel andelution with 2.5%

ethyl acetate in benzene gave, on ether trituration of the combinedfractions, 2a,4,6-1IiChlOtO1701.,21-dihY-droxy-16a-methylpregna-4,6-diene-3,20-dione 2l-acetate which uponcrystallization from methylene chloride-ether melted at 199.5-201.

Elution with 10% ethyl acetate in benzene gave 4,6-dichloro-17u,21-dihydroxy-1fiwmethylpregna 4,6-diene- 3,20-dione21-acetate which upon crystallization from methylene chloride-ethermelted at 189.5-190.

Example 45 To 18.25 g. of6,8-chloro-1711.2l-dihydroxy-l6p-methylpregn-4-en-3,20-dione 21-acetatein 390 ml. absolute ethanol and 390 ml. anhydrous dioxane was added 20.8ml. triethyl orthoformate and 1.30 g. p-toluenesulfonic acidmonohydrate. The reaction mixture was stirred at room temperature undernitrogen in the dark for 2 /2 hours. The reaction mixture was thencooled in an ice bath, 13 ml. of pyridine was added and the mixture wasconcentrated to ca. 200 ml. under reduced pressure. Water (1 liter) wasadded with stirring and the resultant solid was filtered and washed wellwith water to yield 21-acetoxy-6-chloro-3-ethoxy-l7a-hydroxy 16/3methylpregna-3,5-dien-20-one which upon crystallization from aqueousmethanol containing 0.5 ml. of pyridine yielded 12.29 g. melting at147-448. This enol ether (12.29 g.) was added in one portion to asuspension of 60.5 g. of activated manganese dioxide in 650 ml. ofacetic acid and 55 ml. of water. After stirring under a nitrogenatmosphere at room temperature for 3 hours, the manganese dioxide wasremoved by filtration through a filter aid. The filtrate wasconcentrated to dryness under vacuum to an oil which was taken up inchloroform, washed with 5% sodium bicarbonate, 1 N hydrochloric acid andwith water. Concentration of the dried (MgSO' extract gave a yellowsolid (8.26 g.). Two crystallizations of the crude product from ethylacetate-hexane yielded 6-chloro-17a,21-dihydroxy 16,8-methylpregna-4,6-diene-3,20-dione 21-acetate melting at 201.5-203".

Example 46 To 4.346 g. of6-chloro-17a,21-dihydroxy-16B-methylpregna-4,6-diene-3,ZO-dione21-acetate in 40 ml. of chloroform (filtered through silica gel toremove alcohol) at 0 was added rapidly 11.0 ml. (0.011 mole; 1.0 molar)of a solution of chlorine in carbon tetrachloride. After 2 hours at 3,solvents were removed under reduced pressure and the resultant foam wastreated with 25 ml. of pyridine. After the reaction mixture stood atroom temperature for 2 hours, the pyridine was removed under vacuum andthe residue was taken up in methylene 28 chloride, washed with 2 Nhydrochloric acid, water, dried (MgSO and concentrated under reducedpressure to yield4,6-dichloro-17u,21-dihydroxy-16/8-methylpregna-4,6-diene-3,20-dione21-acetate as a crude solid which upon two crystallizations frommethylene chlorideether melted at 196-1975 Example 47 To a solution of3.9 g. of 6-chloro-l7a-acetoxy-16- methylenepregna-4,6-dien-3,20-dionein 25 ml. of alcohol-free chloroform was added dropwise (at 0) 11.3 ml.(5 %excess) of a 0.87 molar solution of chlorine in carbontetrachloride. The resultant solution was stirred for one hour at 0 andthe solvents were then removed under reduced pressure. The resultingfoam was treated with 10 ml. of dry pyridine and then stirred at roomtemperature for 2 hours. Ether (200 ml.) was added and the mixture wastwice extracted, each time with 150 ml. of 1 N hydrochloric acid. Theether solution was then dried and the solvent was removed under reducedpressure. The residue was triturated with ether to give 2.4 g. ofmaterial which was chromatographed on g. of silica gel. Elution with 2%ethyl acetate'benzene gave 20c,4,6-tIiChlO1O-17uacetoxy-l-methylenepregna- 4,6-dien-3,20-dione which uponcrystallization from methylene chloride-ether melted at 235238 d. (dec.begins 225).

Further elution with 5% ethyl acetate-benzene gave4,6-dichloro-17a-acetoXy-l6-methylenepregna 4,6-dien- 3,20-dione whichupon crystallization from methylene chloride-ether melted at 2l8219.

Example 48 A solution of 0.250 g. of 2oz,4,6-trichloro-l7a-acetoxy-16-methylenepregna-4,6-dien-3,20-dione, 0.1 g. of lithium chloride, and3 ml. of dry dimethylformamide was refluxed for one half hour under anitrogen atmosphere. The solution was then cooled and poured into 100ml. of ice water. The product was filtered and air-dried. Theso-obtained crude material was chromatographed on 6 g. of neutralalumina (grade I). Elution with a 1:1 solution of petroleum ether(60-90") and methylene chloride and finally methylene chloride gave4,6-dichloro-l7uacetoxy-l6-methyleuepregna-1,4,6triene-3,20-dione as alight yellow product which upon crystallization from ether-methylenechloride melted at 225-228.

Example 49 To a solution of 0.5 g. of 4,6-dichloro-17a-acetoxy-16-methylenepregna-4,6-dien-3,20-dione in 10 ml. of dry tetrahydrofuran wasadded dropwise a solution of 1.3 g. of lithium aluminumtri-tert-butoxyhydride in 10 ml. of dry tetrahydrofuran. After stirringfor 2 hours at room temperature the solution was cooled in an ice bathand 1.0 ml. of acetone was added. After 15 minutes the solution waspoured into 150 m1. of chloroform and the chloroform solution was twiceextracted, each time with ml. of 10% acetic acid solution, then with 5%sodium bicarbonate solution. The aqueous washings were combined andextracted with ether. The combined organic layers were dried and thesolvent was removed under reduced pressure giving4,6-dichloro-3B,l7u-dihydroxy-16- methylenepregna-4,6-dien-20-one17-acetate which upon crystallization from methylene chloride-ethermelted at 220-222.

Example 50 A solution of 0.5 g. of 4,6-dichloro-3fl,17a-dihydroxy-16-methylenepregna-4,6-dien-20-one 17-acetate, 5 ml. of distilled aceticanhydride, and 5 ml. of pyridine was stirred overnight at roomtemperature. The reaction mixture was then poured into 200 ml. of icewater and the product which precipitated was filtered and air-dried,yielding crude4,6-dichloro-3fi,17a-diacetoxy-16-methylenepregna-4,6-diene-20-one whichupon crystallization from methylene chloride-ether melted at 227.5229.

29 Example 51 To 1.05 g. of6-chloro-16u,17a-isopropylidenedioxypregna-4,6Pdiene-3,20-dine in 10 ml.of alcohol-free chloroform at 0 is added 2.8 ml. of 1.0 M solution ofchlorine in carbon tetrachloride. After 1 hour at 3, solvents areremoved under reduced pressure and the residue treated with 12 ml. ofpyridine. After standing at room temperature for 2 hours, the pyridineis removed under vacuum and the residue taken up in methylene chloride,washed with 2 N hydrochloric acid, water, dried (MgSO and concentratedunder reduced pressure. The residue is chromatographed on silica gel andthe purified product is recrystallized from acetone/hexane to yield4,6-dichloro 16a,17oc isopropylidenedioxypregna-4,6-diene- 3,20-dione.

Example 52 To a solution of 3.78 g. of6-chloro-6-dehydro-17eethoxyprogesterone in 30 ml. of alcohol-freechloroform is added (at 0) 13 ml. of a 0.8 molar solution of chlorine incarbon tetrachloride. The reaction mixture is allowed to stand for onehour at 0. The solvent is then removed under reduced pressure and theresidue treated with 5 ml. of dry pyridine. After one hour at roomtemperature 200 ml. of ether is added and the mixture washed with 1 Nhydrochloric acid solution. This ether solution is then dried overmagnesium sulfate and the solvent removed under reduced pressure.Chromatographic purification of the residue on silica gel, followed bycrystallization of the product from methylenechlorideether gives4,6-dichloro-6-dehydro-l7a-ethoxyprogesterone.

Example 53 To a cooled (30) solution of 500 mg. of 6-chloro-2l-fluoro-17u-methyl-6-dehydroprogesterone in 7 ml. of ether, 3 ml. ofdichloromethane and 10 ml. of dimethylformamide is added 1.31 mmoles ofchlorine in propionic acid solution. The resultant solution is thenallowed to stand at for 18 hours and then at room temperature for 6hours. The resulting mixture is poured into 200 ml. of Water and isextracted three times with etherdichloromethane (2.5 :1). The organiclayers are washed once with 5% sodium bicarbonate solution, once withbrine, dried, and evaporated. The residue is crystallized from ether andrecrystallized from dichloromethaneh'exane to give4,6-dichloro-21-fluoro-17a-methyl-6-dehydroprogesterone.

Example 54 A solution of 400 mg. of 6-0111010-lulu-11161131161166-dehydro-17a-acetoxyprogesterone in 10 ml. of 1:1 mixture ofdichloromethane-ether is cooled to and 1.0

mole of a freshly prepared solution of chlorine in propionic acid isadded. After 3 hours at l5, the resultant solution is poured into sodiumbisulfite solution and is extracted with dichloromethane. This extractis washed with water, dried, and concentrated. The residue is dissolvedin 5 ml. of pyridine and is heated at 45 until thin layer chromatographyshows that the reaction is complete. The mixture is then diluted withdichloromethane and ether and the organic layer is washed with 0.5 Nhydrochloric acid solution, water, 5% sodium bicarbonate solution and isthen dried and evaporated. The residue is dissolved in dichloromethaneand purified by chromatography through a column of silica gel. Theproduct crystallizes from dichloromethane-hexane and is recrystallizedfrom dichloromethane-hexane to give 4,6-dichloro-la,2a-methylene-6-dehydro-17u-acetoxyprogesterone.

Example 55 A solution of 480 mg. of6-chloro-6-dehydro-17u-ethylprogesterone in 6 ml. of ether and 4 ml. ofdichloromethane is cooled to 25 and 1.41 mmoles of chlorine in apropionic acid solution (freshly prepared and standardized) is added.The resultant mixture is kept at 15 overnight and is then diluted withdichloromethane and washed with aqueous sodium bisulfite solution,water, dried and concentrated. The residue is dissolved in 7 ml. ofpyridine and is allowed to stand at room temperature for 24 hours. Thereaction mixture is diluted with ether and the organic layer is washedwith 1 N hydrochloric acid solution, 5% sodium bicarbonate solution,water and then dried and concentrated. The residue is crystallized fromether and recrystallized from acetone-hexane to give4,6-dichloro-6-dehydro-l7u-ethylprogesterone.

Example 5 6 A mixture containing 2 g. of 6a-fluoro-16u,17a-isoprwpylidenedioxy-4-pregnene-3,11,20-trione, 2 g. of chloranil and ml. oft-butyl alcohol is refluxed for 18 hours. The cooled solution is dilutedwith 300 ml. of chloroform, washed three times with cold 5% sodiumhydroxide solution, water, and is then dried over magnesium sulfate. Thesolvent is removed under reduced pressure and the crude6-fiuoro-l6a,l7a-isopropylidenedioxypregna 4,6 diene- 3,l1,20-trione ispurified by chromatography on neutral alumina followed bycrystallization from methylene chloride-ether.

According to the above procedure treatment of: 1) 21- acetoxy 6a fluoro16a fluoromethyl 17oz hydroxy- 4-pregnene-3,ll,20-trione yields2l-acetoxy-6-lluoro-l6afluoromethyl 17a hydroxypregna-4,6 diene 3,11,20-trione; (2) 6u-fluoro-16u,17a,21-trihydroxy 4 pregnene- 3,11,20-trioneyields 6-fiuoro-16a,l7a,2l-trihydroxy-pregna-4,6-diene-3,11,20-trione;(3) 21 acetoxy-6a,l6u-difluoro 17cc hydroxy 4 pregnene 3,11,20 trioneyields 21 acetoxy 6,160: difluoro 17a hydroxypregna-4,6-diene-3 ,11,20-trione.

To a solution of 4.16 g. of 6-fiuoro-16a,l7a-isopropylidenedioxypregna4,6 diene 3,11,20 trione in 50 ml. of alcohol-free chloroform is added(at 0) 17 ml. of a 0.6 molar solution of chlorine in carbontetrachloride. The reaction mixture is allowed to stand for one hour at0. The solvent is then removed under reduced pressure and the residue istreated with 6 ml. of dry pyridine. After one hour at room temperatureether (200 ml.) is added and the mixture is washed with 1 N hydrochloricacid solution. The ether solution is dried over magnesium sulfate andthe solvent is removed under reduced pressure. Chromatographicpurification of the residue on silica gel followed by crystallization ofthe product from methylene chloride-ether gives4-chloro-6-fiuoro-16u,l7x-isopropylidenedioxypregna-4,6-diene-3 ,11,20-trione.

According to the above procedure chlorination of: (1) 21 acetoxy 6fluoro 16oz fluoromethyl 17o: hydroxy-pregna-4,6-diene-3,l1,20-trioneyields 21-acetoxy- 4-chloro 6 fluoro 16cc fluoromethyl 17ozhydroxypregna-4,6-diene-3,l1,20-trione; (2) 6-fluoro 16cc,170c,21-trihydroxy pregna 4,6 diene 3,11,20 trione yields 4 chloro 6 fluoro16a,170c,21 trihydroxy-pregna- 4,6-diene-3,l1,20-trione; (3) 2l-acetoxy6,16a difiuoro- 17a hydroxy pregna 4,6 diene 3,11, 20 trione yields 21acetoxy 4 chloro 6,16 difluoro 17a hydroxypregna-4,6-diene-3,11,20-trione.

Example 57 To a solution of 2.25 g. of4-ChlO1'0-6-fiIlOI'O-l6oc,l7aisopropylidenedioxypregna-4,6-diene 3,11,20trione dissolved in 75 ml. of dry tetrahydrofuran is added dropwise asolution of 3.8 g. of lithium aluminum tri-tertiary butoxy hydridedissolved in 30 ml. of dry tetrahydrofuran. The resultant solution isstirred for 2 hours at room temperature and is then cooled to 0".Acetone (2 ml.) is then added and the solution is stirred for anadditional fifteen minutes. The cooled mixture is then diluted with 300ml. of chloroform and the chloroform solution is Washed with a 10%acetic acid solution followed by 5% sodium bicarbonate solution and isthen dried over magnesium sulfate. The solvent is removed under reducedpressure and the residue is crystallized from methylene chlo- 31ride-ether to give 4chloro-6-fiuoro-l6u,17a-isopropylidenedioxypregna-4,6-diene-3,G-ol-11,20-dione.

A mixture of 3 g. of 4-chloro-6-fluoro-16u,17a-ispropylidenedioxypregna4,6 diene 3/3 o1 11,20 dione, 30 m1. of dry pyridine and 30 ml. ofacetic anhydride is stirred for 18 hours at room temperature. Thesolution is then poured into 200 ml. of ice water and the product isfiltered. Crystallization from methylene chloride-methanol gives 318acetoxy 4 chloro 6 fluoro 16a,17a isopropylidenedioxypregna-4,6-diene-11,20-dione.

Example 58 To 2.11 g. of 6-chloro-21-fluoro-17a-hydroxypregna-4,6-diene-3,20-dione 17-acetate in 10 ml. of ether and 10 ml. ofdimethylformamide at is added 5.5 ml. of a 1.0 molar solution ofchlorine in propionic acid. The reaction is allowed to stand at l for 12hours and then at room temperature for 5 hours. The resulting mixture ispoured into 200 ml. of water and is extracted three times withether-dichloromethane (2.5: 1). The organic layer is washed with 5%sodium bicarbonate, water, dried (MgSO and concentrated at reducedpressure. The residue is chromatographed on silica gel and the purifiedproduct is recrystallized from acetone/hexane to yield 17a-acetoxy 4,6dichloro 21 fluoropregna- 4,6-diene- 3,20-dione.

Example 59 A mixture of 15 g. of16a-chloromethyl-l7a-acetoxyprogesterone, 150 ml. of dioxane (purifiedover alumina),

20 ml. of triethyl orthoformate, 10 ml. of ethanol and 1.5 ml. ofconcentrated sulfuric acid is stirred at room temperature in the absenceof light. After 2 hours the reaction mixture is poured with stirringinto 3 liters of ice and water containing excess sodium bicarbonate. Theresultant precipitate is collected by filtration, washed well with waterand dissolved in dichloromethane. This solution is dried andconcentrated to a semisolid residue which could be crystallized fromether to give17a-acetoxy-16uchloromethyl-3-ethoxypregna-3,5-diene-20-one but whichnormally is used directly for the next reaction.

According to the above procedure treatment of (l) 21 acetoxy 17a hydroxy16 methylene-4-pregnene- 3,11,20-trione yields 21-acetoxy 3 ethoxy 17ozhydroxy 16 methylene pregna 3,5 diene-11,20-dione; (2)17w(2-chloroethynyl)-17B-hydroxy androst 4 ene- 3-one yields17a-(2-chloroethynyl) 3 ethoxy-17fl-hydroxy-androsta-3,S-diene.

A solution of the foregoing crude enol ether prepared from 15 g. of 16ozchloromethyl-17a-acetoxyprogesterone in 670 m1. of acetone is cooled to5. A solution of 14.2 g. of sodium acetate in 240 ml. of water is addedthereto, followed by 27.6 g. of N-chlorosuccinimide and 17.2 ml. ofacetic acid. After stirring for an additional 1.5 hours the reactionmixture is poured into 8 liters of water and ice. After stirring for anadditional hour the slurry is filtered and the precipitate is dissolvedin dichloromethane and dried. Removal of the solvent and crystallizationof the residue from dichloromethane-ether gives 6i3-chloro-16a-chloromethyl-17a-acetoxyprogesterone.

According to the above procedure treatment of: (1) 2l-acetoxy 3 ethoxy17a hydroxy 16 methylenepregna-3,5-diene-11,20-dione yields21-acetoxy-6fi-chlorol7ot-hydroxy-l6-methylene 4 pregnene3,11,20-trione; (2) 17oz (2 chloroethynyl) 3 ethoxy 175 hydroxyandrost3,5 diene yields6B-chloro-17a-(2-chloroethynyl)-17fl-hydroxy-androst-4-ene-3-one.

A mixture of 10.0 g. of the foregoing '6/3-chloro compound, 50 ml. oftetrahydrofuran (purified over alumina), 18 ml. of triethylorthoforrnate, 5 ml. of ethanol and 100 mg. of p-toluenesulfonic acid isstirred at room temperature for 1.5 hours in the absence of light. Thereaction mixture is then added in the course of 10 minutes to a stirredsuspension of g. of activated manganese dioxide in 450 ml. of aceticacid and 35 ml. of water. The re sultant mixture is stirred for anadditional hour and then filtered. The solid is washed well withdichloromethane and the combined filtrates are concentrated undervacuum. The oily residue is diluted with dichloromethane, washed threetimes with 5% sodium bicarbonate solution, once with water, dried andconcentrated. The residue is crystallized with ether and thenrecrystallized from acetonehexane to give purified6-chloro-l6a-chloromethyl-6-dehydro-17a-acetoxyprogesterone.

According to the above procedure treatment of: (1) 21- acetoxy 65chloro-l7a-hydroxy 16 methylene-4- pregnene-3,11,20-trione yields21-acetoxy-6-chloro-17ahydroxy-l6-methylene-pregna 4,6diene-3,11,20-trione; (2) 6fi-chloro 17a (2chloroethynyl)-l7}3-hydroxyandrost 4 ene 3 one yields 6chloro-17a-(2-chloroethynyl l 7fl-hydroxy-androsta-4,6-diene-3-one.

A solution of 1.00 g. of 6-chloro-16a-chloromethyl6-dehydro-17a-acetoxyprogesterone in 22 ml. of dimethylformamide and 11ml. of ether is cooled to 0 and 2.55 mmoles of chlorine in a propionicacid solution is added. The resultant solution is kept in therefrigerator for 12 hours and then at room temperature for 8 hours. Thesolution is then diluted with 2:5 dichloromethane-ether and washed withwater, 5% sodium bicarbonate solution, water, dried and evaporated. Theresidue is crystallized from dichloromethane-hexane to give purified4,6-dichloro-16a-chloromethyl-6-dehydro-17a-acetoxyprogesterone.

According to the above procedure chlorination of (l)21-acetoxy-6-chloro-17a-hydroxy 16 methylene-pregna-4,6-diene-3,l1,20-trione yields 21 acetoxy-4,6-dichloro- 17a-hydroxy 16rnethylene-pregna-4,6-diene-3,l1,20- trione; (2)6-chloro-17a-(2-chloroethynyl)-17;3-hydroxyandr0sta-4,6-diene-3-oneyields l7ot-(2-chloroethynyl)-4,6-dichloro-17fl-hydroxy-androSta-4,6-diene-3-one.

Example 60 To 1.051 g. of 6-chloro-17a-acetoxy-l6a-methylpregna-4,6-diene-3,20-dione in 10 ml. of alcohol-freechloroform at 0 was addedrapidly 2.97 ml. (0.00276 mole) of a 0.93 M solution of chlorine incarbon tetrachloride. After 1 hour at 3, solvents were removed underreduced pressure and the crude product was treated with 6.5 ml. ofpyridine. After standing at room temperature for 1 hour, the pyridinewas removed under vacuum and the residue was taken up in methylenechloride, washed with dilute hydrochloric acid and water. The organiclayer was dried (MgSO concentrated under reduced pressure, and the crudeproduct was chromatographed on 30 g. of silica gel. Elution of theproduct with 5% ethyl acetate in benzene and recrystallization of thecombined fractions from ethyl acetate-hexane gave purified4,6-dichloro-l7u-hydroxy- 16a-methylpregna-4,6-diene-3,2'0-dioneacetate, MP. 173;

max.

A solution of 0.300 g. of4,6-dichloro-17u-acetoxy-l6amethylpregna-4,6-diene-3,20-dione in 10 ml.of anhydrous tetrahydrofuran was added dropwise over a l5-minute periodof 0.511 g. (2.0 mmole) of lithium aluminum tri-tbutoxyhydride in 7 ml.of anhydrous tetrahydrofuran under a nitrogen atmosphere. After stirringat room temperature for 2 hours, 3 ml. of acetone was added followed by1 ml. of water. The mixture was then concentrated under reduced pressureand 30 ml. of chloroform was added, followed by 30 ml. of 10% aceticacid in water. The resultant organic layer was washed with 5% sodiumbicarbonate solution, dried (MgSO and concentrated under reducedpressure. Crystallization of the residue from acetone-hexane gave4,6-dichloro-3B,l7a-dihydroxy-16amethylpregna-4,6-diene-20-one17-acetate which upon a second crystallization from acetone-hexanemelted at 1880-1915,

AELOH max.

33 Example 62 To a cooled and stirred solution of 64.0 g. of 165 methyl110t,17ot,21 trihydroxy-5a-pregnane-3,20- dione 2l-acetate in 70 ml. ofacetic acid and 700 ml. of dry dioxane, was added dropwise, over a-minute period 340 ml. of 0.92 molar solution of bromine in acetic acid.The reaction mixture was allowed to stir rapidly at 5-l0 for 45 minutesand was then poured into 8 liters of Water containing 98.0 g. of sodiumacetate. The crystalline product was filtered, washed with water anddried under vacuum to give 79.0 g. of 25,45-dibromo-l6fi-methyl-lla,l7a,2l-trihydroxy 5oz pregnane-3,20-dione 2l-acetate, melting point124128.

A solution of bromoacetone was prepared by adding rapidly 40 ml. ofreagent grade bromine to 1200 ml. of acetone at 5. After minutes, 240 g.of anhydrous potassium carbonate was added and the mixture was allowedto stir at 5 for an additional 45 minutes. The reaction mixture wasfiltered and the filtrate stored in the refrigerator for use asdescribed below.

To a stirred solution of 65-0 g. of sodium iodide in 2500 ml. of acetonewas added 1100 ml. of freshly prepared bromoacetone solution. Thestirred mixture was heated under reflux (nitrogen atmosphere) for 15minutes and then a solution of 79.0 g. of 2,4-dibromo-l6{3-methyl-11a,l70:,21-trihydroxy-5a-pregnane 3,20 dione 21-acetate in 500ml. of acetone was added dropwise over aS-minute period. The reactionmixture was stirred under reflux for 2% hours, and then a solution of79.0 g. of oxalic acid in 500 ml. of acetone was added over a 5- minuteperiod. The reaction mixture Was stirred under reflux for an additional45 minutes. The mixture was diluted with 3 liters of ethyl acetate,stirred for 5 minutes, filtered, and the residue was washed with 500 ml.of ethyl acetate. The filtrate was washed with 1500 ml. of water, 5%NaHCO (1500 ml.) and brine (1500 ml.). The aqueous layers were extractedwith two liters of ethyl acetate. The organic layers were then combinedand dried over sodium sulfate.

- To the dried ethyl acetate solution was added 250 ml. of glacialacetic acid followed portionwise with 250 g. of zinc dust. The mixturewas cooled to room temperature and was stirred for 45 minutes. Thereaction mixture was then filtered and the residue was washed withmethylene chloride. The filtrate was washed with water, 5% sodiumbicarbonate solution (1500 ml.) and brine (2000 ml.). The organic layerwas dried over sodium sulfate, filtered and concentrated under vacuum.The residue was crystallized from acetone to give 19.70 g. of16B-methyl- 1 1 a,17oz,2 l-trihydroxypregn-4-ene3,20-dione 21-acetate,

melting point 233-240.

Example 63 To a solution of 28.0 g. ofl6B-methyl-11u,17a,21-trihydroxypregn-4-ene-3,20-dione 2l-acetate in 550ml. of dry dioxane and 550 ml. of absolute alcohol was added 33.0 ml. oftriethyl orthoformate and 2.0 g. of p-toluene sulfonic acid. Thereaction mixture was stirred in the dark at room temperature (nitrogenatmosphere) for two hours and was then diluted with 2.5 liters of watercontaining 10 ml. of pyridine. The mixture was extracted three timeswith etherzmethylene chloride (4:1) and the organic layers were washedtwice with water and were then combined, dried (Na SO and concentratedunder reduced pressure to yield 30.0 g. of crude 3-ethoxy-l6fl-methyl-11a,17a,2 1-trihydroxy-pregna-3,S-diene 2l-acetate.

To a stirred solution of 30.0 g. of so-prepared crude 3- ethoxy 16Bmethyl-lla,l7a,2l-trihydroxy-pregna-3,5- diene 2l-acetate in 535 ml. ofacetone was added a solution of 10.60 g. of sodium acetate in 170 ml. ofwater. The mixture was cooled (5), and 19.50 g. of N-chlorosuccinimidewas added followed by 10.6 ml. of glacial acetic acid. The reactionmixture was stirred at 5 for 70 minutes and was then diluted with twoliters of water. The mixture was extracted three times withetherzmethylene chloride (3:1). The organic layers were washed once with5% sodium bicarbonate solution, three times with water and once withbrine. The organic layers were combined, dried (Na SO and concentratedto yield 37.0 g. of a crude oil which was purified by chromatography on700 g. of synthetic magnesia-silica gel (Florisil, available from TheFloridin Company, Box 989, Tallahassee, Fla.) in benzene. Elution withbenzenezethyl acetate yielded 30.0 g. of the crude6/i-chloro-l6B-methyl-lla,l7a,2l-trihydroxypregn-4-ene-3,20-dione21-acetate.

To a solution of 30.0 g. of the so-prepared crude 6B- chloro 16 3methyl-l1a,17,2l-trihydroxy-pregn-4-ene- 3,20-dione 21-acetate in 600ml. of dry dioxane and 600 ml. of absolute alcohol was added 34.5 ml. oftriethyl orthoformate and 3.45 g. of p-toluene-sulfonic acid. Thereaction mixture was stirred in the dark at room temperature (nitrogenatmosphere) for minutes and was then diluted with 2.5 liters of watercontaining 10 ml. of pyridine. The mixture was extracted three timeswith ether and the ether layers were washed twice with water. Theorganic layers were combined, dried (Na SO and concenrated under reducedpressure to yield 32.0 g. of an oil which was purified by chromatographyon 600 g. of synthetic magnesia-silica gel (Florisil, available from TheFloridin Company, Box 989, Tallahassee, Fla.). Elution withbenzene-ethyl acetate gave 23.0 g. of '6-chloro-3- ethoxy 16,3methyl-1la,17u,21-trihydroxy-pregna-3,5- diene-20-one 2l-acetate,sufliciently pure for the next step.

To a solution of 23.0 g. of the so-prepared 6-chloro-3- ethoxy 16 8methyl 1la,17u,2l-trihydroxy-pregna-3,5- diene-20-one 21-acetate in 920ml. of glacial acetic acid and 75 ml. of water was added 81.0 g. ofactivated manganese dioxide. The reaction mixture was stirred at roomtemperature in the dark (nitrogen atmosphere) for 3% hours and was thenfiltered. The filtrate was evaporated to dryness and the residue wasdissolved in chloroform. The organic layer was washed once with water,twice with 5% sodium bicarbonate solution, once with 1 N hydrochloricacid solution and once with brine. The organic layers were combined,dried (Na SO and evaporated yielding 20 g. of an oil which wastriturated with ethyl acetate and ether to give 6.10 g. of6-ChlOI011ot,17a, 21 trihydroxy-l6fl-methylpregna-4,6-diene-3,20-dione21- acetate which upon crystallization from acetone-ether melted atZOO-200.5

Example 64 To a cooled solution (0) of 0.40 g. of 6-chlorol1a,l7a,21trihydroxy-l6 3-methylpregna-4,6-diene-3,20- dione 2l-acetate in 25 ml.of chloroform was added 0.86 ml. of a 1.15 molar solution of chlorine incarbon tetrachloride. The mixture was maintained at 0 for 30 minutes andthe solvents were then removed under reduced pressure. Pyridine (2.5ml.) was added to the residue and the mixture was allowed to stand at 25for 70 minutes. The pyridine was then removed under reduced pressure andthe resulting crude oil was dissolved in methylene chloride. The organiclayer was washed twice with 1 N hydrochloric acid solution and once withwater. The organic layer was then dried (Na SO and concentrated underreduced pressure to give an oil which was chromatographed on 15.0 g. ofsilica gel. The column was eluted with benzene-ethyl acetate giving 272mg. of an oil which crystallized on addition of ether. The solvent wasremoved and the crude solid was crystallized from methylenechloride-ether yielding 4,6 dichloro-llu,l7a,2l-trihydroxy- 16Bmethylpregna-4,6-diene-3,20-dione 2l-acetate, M.P. 198.5200.5 (dec.);Amax, 300 mu. (6 18,000); [a] +229.2 (c. 0.53 in CHCI Example 65 To astirred solution of 0.50 g. of 4,6diChlOl'O-l1a,l7a,21-trihydroxy-16B-methylpregna-4,6-diene-3,20-dione 21- acetate in 20ml. of acetone, cooled to 5, is added 1.0 ml.

of a chromic acid solution (a stock solution is prepared by dilutingwith water a solution of 26.72 g. chromium trioxide in 23 ml. ofconcentrated sulfuric acid to a final volume of 100 ml.). The resultingmixture is stirred at for an additional minutes and the excess chromicacid is then decomposed by the addition of a few drops of isopropanol.The reaction mixture is then diluted with water and is extracted threetimes with ether-methylene chloride (3:1). The organic layer is washedwith 5% sodium bicarbonate solution and water. The combined organiclayers are dried (Na SO and evaporated under reduced pressure. Theresidue is crystallized from acetone-ether to give 4,6dichloro-17a,2l-dihydroxy-16B-methylpregna-4,6-diene-3,11,20-trione2l-acetate.

According to the above procedure 4,6 dichloro-90tfluoro 11B,l7a,21trihydroxy-l6fi-methylpregna-4,6-diene-3,20-dione 2l-acetate is oxidizedto 4,6-dichloro-9afluoro 17a,21 dihydroxy 16p-methylpregna-4,6-diene-3,1 1,20-trione 21-acetate.

Example 66 To a solution of 0.53 g. of4,6-dichloro-11u,17a,21-trihydroxyl6/8-methylpregna-4,6-diene-3,20-dione 21-acetate in 9 ml. of glacialacetic acid was added dropwise over a 10-minute period 1.25 ml. of a 1.0molar solution of chlorine in acetic acid. The reaction mixture wasallowed to stand at room temperature for 20 minutes and was then dilutedwith 4.0 ml. of water. The resulting precipitate was filtered, Washedwith water and dried to give 2a,4,6-trichloro 11a,17a,21trihydroxy-l6;8-methylpregna-4,6-diene-3,20-dione 2l-acetate, M.P.234236.5, which can be recrystallized from acetone/methanol.

According to the above procedure chlorination of 4,6- dichloro 9ozfluoro-l7a,21-dihydroxy-16B-methylpregna- 4,6-diene-3,ll,20-trione21-acetate yields 211,4,6-tfi6h1010- 9afluoro-17a,2l-dihydroxy-16B-methylpregna-4,6-diene- 3,11,20-trione21-acetate.

Example 67 A solution of 4.0 g. of2a,4,6-tliCh1OIO-11a,17a,21-l11ihydroxy 16B methylpregna 4,6diene-3,20-dione 2lacetate and 0.85 g. of lithium chloride in 85 ml. ofdimethylformamide was heated under reflux for 30 minutes. The reactionmixture was then cooled, diluted with one liter of water and theresulting precipitate was filtered, Washed with water and dried. Theproduct was purified by chromatography on silica gel. Elution with amixture of benzene and ethyl acetate (2:3) gave 4,6-dichloro-11rx,17a,21-trihydroxy 16/3 methylpregna-1,4,6-triene- 3,20-dione2l-acetate.

According to the above procedure treatment of 2a,4,6- trichloro 9ozfluoro-17a,21-dihydroxy-1fifi-methylpregna-4,6-diene-3,l1,20-trione2l-acetate with lithium chloride in dimethylformamide yields4,6-dichloro 9a fluoro-17a,2l-dihydroxy 16B methylpregna 1,4,6 triene-3,11,20-trione 21-acetate.

Example 68 A stirred solution of 2.0 g. of 4,6-diCh10l'O-11a,l7oz,21-trihydroxy 16B methylpregna 1,4,6 triene-3,20-dione 2l-acetate in ml. ofpyridine was cooled to 5 and 1.0 ml. of methanesulfonyl chloride wasadded over a 5-minute period. The reaction mixture was allowed to stir30 minutes longer at 5 and then for 1 hour at room temperature. Thereaction mixture was poured into 250 ml. of cold water and extractedthree times with ethermethylene chloride (3:1). The organic layers werewashed twice with 1 N hydrochloric acid solution, once with 5% sodiumbicarbonate solution and once with brine. The combined organic layerswere dried (Na SO and evaporated to give 4,6-dichloro 11a,17a,21trihydroxy 16,3 methylpregna 1,4,6 triene-3,20-dione 11- mesylateZI-acetate.

36 Example 69 A solution of 2.0 g. of 4,6-dichloro 11a,17a,21 trihydroxy16B methylpregna 1,4,6 triene-3,20-dione ll-mesylate 2l-acetate and 6 g.of sodium acetate in 40 ml. of glacial acetic acid was heated underreflux for one hour. The cooled reaction mixture was poured into ml. ofcold water and the resulting precipitate was filtered, Washed with waterand dried. The product was purified by chromatography on silica gel togive 4,6-dichloro- 17a,2l-dihydroxy 16Bmethylpregna-1,4,6,9*(11)-tetraene-3,20dione 21-acetate.

Example 70 To a stirred solution of 1.0 g. of 4,6-dichloro-17a,21-dihydroxy 16/3 methylpregna 1,4,6,9(l1) tetraene- 3,20-di0ne 2l-acetatein 25 ml. of tetrahydrofuran is added 4.7 ml. of aqueous 0.46 Nperchloric acid followed by 0.40 g. of N-bromoacetamide. The mixture isstirred in the dark at 25 for 4 hours and is then treated with enoughsaturated aqueous sodium sulfite solution to discharge the excesshypobromous acid. The reaction mixture is poured into cold water and theresulting precipitate is filtered, washed with Water and dried to give9a-brorno- 4,6-dichloro-l1,8,17a,2l-trihydroxy 16,3methylpregnal,4,6-triene-3,20-dione 21-acetate.

Example 71 To a stirred and cooled (0-5) solution (nitrogen atmosphere)of 9a-bromo 4,6 dichloro-1l/3,17a,2l-trihydroxy 16B methylpregna 1,4,6triene 3,20 dione 2l-acetate (0.84 g.) in 42 ml. of methanol-chloroformmixture (3:2) is added dropwise 1.5 m1. of 1 N sodium hydroxide solutionover a one-hour period. Stir-ring is continued -for an additional 2hours and the mixture is then neutralized by the addition of aceticacid. The solution is concentrated under reduced pressure to about 5 ml.and 40 ml. of cold water is added with stirring. The resulting productis filtered, washed with water and dried. Chromatographic purificationon a column of silica gel gives 4,6-dlCh'lOl'O-170:,21-dihYdl0XY 9,115oxido-16p-methylpregna-l,4,6-triene-3,20-dione.

Example 72 To 2.5 ml. of 70% aqueous hydrogen fluoride (cooled to 30) ina polyethylene flask is added, portionwise and with stirring, 0.5 g. of4,6-dichloro-17a,21-dihydroxy- 9,11/3-oxido methylpregna 1,4,6triene-3,20- dione. The temperature is maintained at 20 to --30 andstirring is continued for a total of 4 hours. The reaction mixture isthen poured into a solution of 8.75 g. of potassium carbonate in 10 ml.of water. The resulting precipitate is filtered, washed with water anddried to give 4,6-dichloro 90c fluoro-l1B,17u,21-trihydroxy-16/3-methylpregna-1,4,6-triene3,20-dione.

Example 73 To a solution of 0.25 g. of 4,6 dichloro 9afluorol1B,17a,2l-trihydroxy 16/3 methylpregna 1,4,6 triene-3,20-dione in1.0 ml. of pyridine is added at room temperature 0.25 ml. of aceticanhydride. The reaction is allowed to stand at room temperature for 1.5hours and is then poured into 10 ml. of cold water containing 1.5 ml. ofconcentrated hydrochloric acid. The resulting precipitate is filtered,washed with water and dried. Crystallization from acetone-ether gives4,6-dichloro-9a-fluoro- 11fl,17u,21-trihydroxy 16/3methylpregna-1,4,6-triene- 3,20-dione 2l-acetate.

Example 74 A solution of 0.466 g. of 4,6-dichloro 1711,21 dihydroxy 16Bmethyl-1,4,6,9(ll)-tetraene-3,20-dione 21- acetate in pyridine (4.5 ml.)and dichloromethane (4.5 ml.) is cooled to -50 and is treated with 1.0ml. of a solution of chlorine in carbon tetrachloride (71 mg.chlorine/ml.). The mixture is then warmed to room temperature over a10-minute period. The reaction mixture is diluted with 20 ml. ofmethylene chloride and is washed with water, 2 N hydrochloric acidsolution and water. The combined organic layers are dried (Na SO andevaporated under reduced pressure to give 4,6,9a,11/3-tetrachloro17a,21-dihydroxy 16,3 methylpregna-1,4,6-triene-3,20-dione ZI-acetate.

Example 75 A solution of 20.0 g. of 6-chloro-17a-acetoxy-pregna-4,6-diene-3,20-dione in 200 ml. of dimethylformamide and 100 ml. ofether was cooled to about To this was added 53 ml. of a 1.0 molarsolution of chlorine in propionic acid over 10 minutes. The mixture wasallowed to remain overnight at 0 to +3", 6 hours at room temperature andthen it was diluted with water and extracted with an ether/methylenechloride mixture (2.5/1.0). The organic phase was washed with 5% aqueoussodium bicarbonate solution and dried over sodium sulfate and evaporatedto give 25.5 g. crude product.

The crude product was then chromatographed on 1250 g. of syntheticmagnesia-silica gel (Florisil, available from The Floridin Company, Box989, Tallahassee, Fla.) and eluted with benzene and benzene/ethylacetate mixtures. An early fraction [(2%) ethyl acetate-benzene]aiforded 1.6 g. of a mixture rich in2u,4,6-trichloro17a-acetoxypregna-4,6-diene-3,20-dione. The laterfractions afforded 7.35 g. of the major product,4,6-dichloro-17a-acetoxypregna-4,6-diene-3,20-dione.

The 1.6 g. fraction was rechromatographed on 96 g. of silica gel, usingthe same solvent system as above and 0.64 g. of crude product wasobtained. Trituration with ether yielded 0.27 g. of insoluble whitesolid. Crystallization from methylene chloride/ether afforded2u,4,6-trichloro-17wacetoxy-pregna-4,6-diene-3,20-dione as colorlesscrystals, M.P. 220-226 [dec. and sintering (variable melting point)];[a] +l39 (c. 1.01 in CHCl N53? 301 m (e 17100) Example 76 A solution of4.0 g. of 4,6-dichloro-17a-acetoxy-pregna- 4,6-diene-3,20-dione in 40ml. of glacial acetic acid was treated at room temperature over minuteswith 10.6 ml. (1.15 equivalents) of a 0.948 molar solution of chlorinein acetic acid and allowed to react overnight at room temperature. Thecrude product was isolated by dilution with water and extraction withmethylene chloride in the usual manner to give 4.3 g. of crude product.Chromatography on 129 g. of silica gel, with benzene, afforded from theearly fractions 1.97 g. of solid 2a,4,6-trichloro-17a-acetoxy-pregna-4,6-diene 3,20 dione. A sample wascrystallized from methylene chloride/ether and melted at 228235.5 (dec.,sintering).

Example 77 A solution of 1.2 g. of2a,4,6-trichloro-17a-acetoxypregna-4,6-diene-3,20-dione and 0.25 g. oflithium chloride in 25 ml. of dimethylformamide were refluxed for 30minutes, under nitrogen. The reaction mixture was poured into water andextracted with methylene chloride. The organic phase was washed withwater, dried over sodium sulfate, and the solvent removed in vacuo. Theresidue was chromatographed on 30 g. of alumina (Woelm, activity II,neutral) using benzene and benzene/ methylene chloride, and the crudeproduct was crystallized once from methylene chloride/benzene to give0.81 g. of colorless needles of 17a-acetoxy-4,6dichloro-pregna1,4-6-triene-3,20-dione, M.P. 228-229; [a] +18.0 (c. 0.90 in CHCl A512?233-234 my. (e 13600), 260-263 (e 7900), and 308 mp. (e 9220) Example 78A solution of 500 mg. of 4,6-dichloro-9u-fluoro-1113,17a,2l-trihydroxy-16fl-methylpregna 4,6 diene 3,20-

dione, 300 mg. of trimethyl orthovalerate and 14 mg. ofp-toluenesulfonic acid in 250 ml. of benzene is heated under reflux(Dean-Stark trap) for 90 minutes. The cooled reaction mixture isextracted with 5% sodium carbonate, dried, and concentrated under vacuumto an oil. This residue is crystallized from ether and recrystallizedfrom acetone-hexane containing a trace of pyridine to give the17a,2l-methylorthovalerate of 4,6-dichloro-9a-fluoro-llfi,l7a,2l-trihydroxy 16/3 methylpregn-a-4,6-diene-3,20-dione.

According to the above procedure treatment of 4,6-dichloro-9a-fluoro-11B,17a,21-trihydroxy 16,8 methylpregna-1,4,6 triene3,20 dione with trimethyl orthovalerate and para-toluenesulfonic acidyields 170:,21- methylorthovalerate of 4,6-dichloro 9oz fluoro-l1fi,17a, 21-trihydroxy-1Gfi-methylpregna-l,4,6-triene-3,20-dione.

Example 79 A mixture of 3-50 mg. of the 170:,21-1'I16ihYl01th0- valerateof 4,6-diChl0I0-9oL-flll0IO-11]3,17oz,2l trihydroxy-16fi-methylpregna-4,6-diene-3,20-dione and 5.0 m1. of

a 2% solution of water in acetic acid is stirred at room temperatureovernight. The solution is poured into 100 ml. of ice water. Theresulting precipitate is collected by filtration, washed well with Waterand recrystallized from dichloromethane-hexane to give4,6-dichloro-9afiuoro-l1fl,17a,21-trihydroxy 16/8 methylpregna 4,6-diene-3,20-dione 17-valerate.

According to the above procedure treatment of the 17a,2l-methylorthovalerate of 4,6-dichloro-9a-fluoro-11,B,17u,21-trihydroxy-16/3-methylpregna-l,4,6-triene-3,20 dione yields4,6-dichloro-9a-fiuoro-l1fi,17a,21-trihydroxy 16,6-methylpregna-l,4,6-triene-3,20-dione 17-valerate.

Example 80 A solution of 553 mg. of 4,6-diChlOI0-9m-fil101O-l1B,17u,21-trihydroxy-lfi-methylpregna 4,6 diene 3,20- dione 17-valerate in1 ml. of acetic anhydride and 3 ml. of pyridine is allowed to stand atroom temperature overnight. The reaction mixture is poured into 50 m1.of ice water and stirred at 0 for 1 hour. The resulting precipitate iscollected by filtration, washed with water, dried and recrystallizedfrom dichloromethane-hexane to give 4,6-dichloro-9a-fluoro-11;3,17u,21-trihydroxy-16B- methylpregna-4,6-diene-3,20-dione 17-valerate21-acetate.

According to the above procedure treatment of 4,6-diChlOIO-9oc-fll10IO-l 1;3,17a,21-trihydroxy 163methylpregna-1,4,6-triene-3,20-dione 17-valerate yields 4,6-di-ChlO10-9a-flu0l'O-11B,17oc,21 trihydroxy 16,3methylpregna-l,4,6-triene-3,20-dione l7-valerate 2l-acetate.

Example 81 To a suspension of 1.0 g. of 4,6,9a,11 3-tetrachloro-17a,21-dihydroxy-16B-methylpregna-1,4,6-triene-3,20 dione 21-acetate in 100ml. of methanol is added a solution of 1.0 g. of potassium bicarbonatein 10 ml. of water. The reaction mixture is stirred overnight at roomtemperature and the solution is then diluted with 200 ml. of brine. Theresulting precipitate is filtered, washed with water and dried to give4,6,9a,11fl-tetrachloro 170:,21dihydroxy-16fl-methylpregna-1,4,6-triene-3,20-dione.

Example 82 A mixture of 400 mg. of 4,6,9a,1 1B-tetrachloro-17a,21-dihydroxy-16fl-methylpregna-1,4,6-triene 3,20 dione, 6 ml. of propionicacid and 2.0 ml. of trifluoroacetic anhydride is heated at for 2 hours.The cooled reaction mixture is poured slowly into ml. of ice and water.After stirring the reaction mixture for one hour, the resultantprecipitate is collected by filtration, washed well with water, driedand crystallized from dichloromethanehexane to give4,6,9a,11B-tetrachl0ro-17u,2l-dihydroxy- 16fi-methylpregna-1,4,6-triene3,20 dione 17,21-dipropionate.

Example 83 A solution of 500 mg. of 9a-fiuoro-4,6-dichloro-l1 8,17a,2l-trihydroxy-16B-methylpregna 1,4,6 triene-3,20- dione, 332 mg. ofB-cyanoethyl phosphate and 1.82 g. of N,N'dicyclohexylcarbodimide in 50ml. of dry pyridine is stirred at room temperature for 2 days. Sevenmilliliters of water is added and after standing at 5 for 2 days thesolvents are removed under reduced pressure. The residue is stirred atroom temperature for 2 hours with 200 ml. of 50% methanol and 8.8 ml. of5% sodium hydroxide solution. Dilute hydrochloric acid is added untilthe solution is pH 4 and the mixture is filtered. The filtrate isadjusted to pH 9 with sodium hydroxide. A solution of 450 mg. ofpiperazine acetate in water is added, the precipitate is collected byfiltration, washed well with water and dried to give crude90t-fluOrO-4,6-dlChlOI'O-11}3,170t,21' trihydroxy-l6 8-methylpregna1,4,6 triene-3,20-dione 2l-phosphate piperazinium salt. This material isstirred for one hour with a suspension of excess of polystyrene nuclearsulfonic acid ion exchange resin (Dowex 50-8X) (H+ form) in methanol.The resin is removed by filtration and the solution is concentrated invacuo. The residue is crystallized from acetone-hexane to give9u-fiuoro- 4,6-dichloro-11;8,17a,21-trihydroxy 16,9methylpregnal,4,6-triene-3,20-dione 21-dihydrogen phosphate. Thisdihydrogen phosphate compound is dissolved in water and passed through acolumn containing excess methacrylic carboxylic acid ion exchange resin(Na+ form) (Amberlite IRC-SO). Lyophilization of the eluate then gives9afluoro-4,6-dichloro 11,8,17a,21trihydroxy-16fl-methylpregna-1,4,6-triene-3,20-dione 21-disodiumphosphate as an amorphous solid.

Example 84 A stirred solution of 1.5 g. of 4,6-diChlOIO-l1u,17ot,21trihydroxy-16fi-methylpregna-4,6-diene-3,20-dione 21-acetate in 15 ml.of pyridine was cooled to 5 and 0.75 ml. of methanesulfonyl chloride wasadded over a 5-minute period. The reaction mixture was allowed to stir30 minutes longer at 5 and then for 1 hour at room temperature. Thereaction mixture was then poured into 100 ml. of cold water and wasextracted three times with ether-methylene chloride (3: 1). The organiclayers were washed twice with 1 N hydrochloric acid solution and oncewith water. The combined organic layers were dried (Na SO and evaporatedto give 4,6 dichloro-l1a,17a,21-trihydroxy-l6fl-methylpregna-4,6-diene3,20 dione ll-mesylate 2l-acetate.

. Example 85 A solution of 1.5 g. of4,6-dichloro-1la,17a,21-trihydroxy-16fl-methylpregna-4,6-diene-3,20-dionell-mesylate 2l-acetate and 4.35 g. of sodium acetate in 30 ml. ofglacial acetic acid was heated under reflux for one hour. The cooledreaction mixture was diluted with 70 ml. of cold water and the resultingprecipitate was filtered, washed with water and dried. Onecrystallization from methanol gave4,6-dichloro-17a,2l-dihydroxy-lGfi-methylpregna-4,6,9(11)-triene-3,20-dioneZI-acetate, M.P. 205- 209".

Example 86 To a stirred solution of 0.50 g. of4,6-diChl01O-17a,2ldihydroxy-l6,B-methylpregna-4,6,9(11)triene-3,20-dione ZI-acetate in 10 ml. of tetrahydrofuran was added 4.5ml. of aqueous 0.60 normal perchloric acid followed by 0.50 g. ofN-bromoacetamide. The mixture was stirred in the dark at 30 for 4 hoursand was then treated with enough saturated aqueous sodium sulfitesolution to discharge the excess hypobromous acid. The reaction mixturewas then diluted with cold water and was extracted twice withetherdichloromethane (3:1). The organic layers were washed twice withwater, dried, and concentrated. The residue was dissolved in benzene andpurified over a silica gel column to give 9a-bromo-4,6-dichloro1118,17u,21 trihydroxy- 40 16,8-methylpregna-4,6-diene-3,20-dione 21acetate, M.P. 147-150.

Example 87 To a stirred and cooled (OS) solution (nitrogen atmosphere)of 9abromo-4,6-dichloro-11,6,17a,21-trihydroxy-16/8-methylpregna-4,6-diene-3,20-dione21 acetate (0.84 g.) in 42 ml. of methanolchloroform mixture (3:2) wasadded dropwise 1.5 ml. of 1 N sodium hydroxide solution over a one-hourperiod. Stirring was continued for an additional 2 hours and the mixturewas then neutralized by the addition of acetic acid. The solution wasconcentrated under reduced pressure to a thick slurry and 40 ml. of coldwater was added with stirring. The resulting product was filtered,washed with water and dried. Chromatographic purification on a column ofsilica gel gave 4,6-dichloro- 17a,21-dihydroxy-9,llfi-oxido 165methylpregna-4,6- diene-3,20-dione, M.P. 215-220.

Example 88 To a stirred and cooled (30) solution of 0.04 g. of4,6-dichloro-l7a,21-dihydroxy9,1lB-oxido 16Bmethylpregna-4,6-diene-3,20-dione in 1.0 ml. of chloroform in apolyethylene flask was added 1.0 ml. of 70% aqueous hydrogen fluoride.The resulting mixture was stirred for 6 hours at 20 and was then treatedto at least neutrality with an excess of sodium carbonate solution. Themixture was then extracted with chloroform. The organic layers werewashed with water, combined, dried (Na SO and evaporated. The residuewas chromatographed on silica gel to give4,6-dichloro-9a-fluoro-11,8,17a,21-trihydroxy- 163-methylpregna-4,6-diene-3,20-dione.

Example 89 To a solution of 0.25 g. of 4,6-dichloro-9a-fiuoro-11,3,17a,21 trihydroxy 16B methylpregna-4,6-diene-3,20- dione in 1.0 ml. ofpyridine is added at room temperature 0.25 ml. of acetic anhydride. Thereaction mixture is allowed to stand at room temperature for 1.5 hoursand is then poured into 10 ml. of cold water containing 1.5 m1. ofconcentrated hydrochloric acid. The resulting precipitate is filtered,Washed with water and dried. Crystallization from acetone-ether gives4,6-diChlOIO-9a-flll0l'0-116,17a,21-trihydroxy-l6,Bmethylpregna-4,6-diene 3,20- dione ZI-acetate.

Example 90 To a solution of 0.503 g. of 4,6-dichloro-9ot-fiuoro-11p17a,21-trihydroxy-16fi-methylpregna-4,6-diene-3,20-dione 21-acetate in10 ml. of glacial acetic acid is added dropwise over a 10-minute period1.1 ml. of a 1.0 molar solution of chlorine in acetic acid. The reactionmixture is allowed to stand at room temperature overnight and is thendiluted with ml. of water and is extracted three times withether-methylene chloride (3:1). The organic layers are washed twice with5% sodium bicarbonate solution and once with brine. The combined organiclayer are dried (Na SO and evaporated under reduced pressure. Theresidue is chromatographed on silica gel to give2a,4,6-trichloro-9ot-fluoro-1 1B,17a,2l-trihydroxy-16;8-methylpregna-4,6-diene-3,20-dione 21-acetate.

Example 91 A solution of 0.6 g. of 2a,4,6 trichloro 9a fluoro-11;8,17a,21 trihydroxy 16,6 methylpregna 4,6 diene- 3,20-dione21-acetate and 0.15 g. of lithium chloride in 15 ml. ofdimethylformamide is heated under reflux for 30 minutes. The reactionmixture is then cooled and diluted with ml. of water. The resultingmixture is extracted three times with ether-methylene chloride (3 :1)and the organic layers are washed twice with water and once with brine.The combined organic layers are dried (Na SO and evaporated to drynessunder reduced pressure. The residue is purified by chromatography onsilica gel to give 4,6 dichloro 9oz fiuoro 1lfi,17a,21 trihydroxy 16pmethylpregna 1,4,6 triene 3,20 dione 21-acetate.

